Inbreeding and cognitive ability

From the paper:

Our results show that within a representative UK population sample there was a weak nominally significant association between burden of autosomal runs of homozygosity and higher non-verbal cognitive ability. This nominal association with increased cognitive ability is counterintuitive when compared with the results from more extreme inbreeding based on pedigree information.1, 2, 3 A potential explanation for this direction of effect is that individuals with higher cognitive ability might show greater positive assortative mating, which would lead to increased homozygosity at loci for higher cognitive ability in their offspring. However, in a separate sample we showed that greater positive assortative mating was not associated with higher cognitive ability. While these findings seem to provide clear evidence against this hypothesis, it is possible that the genome-wide genetic findings reflect historical mating habits that no longer exist today. It should also be noted that there was a reduction in the standard deviations for spousal correlations in the increased cognitive ability groups by an average of 6% compared with the decreased cognitive ability group (see Table 3), which could reflect lesser genetic variability in the high ability couples or a ceiling effect on the cognitive tests. This lesser phenotypic variability at the high ability end would have a small effect in reducing the spouse correlations and potentially confound our analysis. 

Genetic variants were found to have a slight (though significant) reduction in minor allele frequency across the genome in individuals in the top quartile of general cognitive ability compared with those in the bottom quartile (means of 21823 and 21824), which in turn could lead to increased homozygosity by chance. This could indicate that these individuals descend from subtly different ancestral populations that experienced loss of variation. This difference in ancestry may be correlated with either genetic variants for improved cognitive ability, or with social or environmental backgrounds that lead to higher cognitive ability, though our analysis of FROH corrected for socio-economic status and population stratification. Another potential explanation is that the reduced minor allele frequency in the high cognitive ability is reflective of the less frequent allele being deleterious due to selection against it. As a result, these high-functioning individuals could benefit from having more major alleles at fixation and a reduced burden of rarer deleterious variants. 

Overall, these results highlight the importance of understanding mating habits, such as inbreeding and assortative mating, when investigating the genetic architecture of complex traits such as cognitive ability. The results certainly suggest that there is no large effect of FROH on reduced cognitive ability, the expected direction of effect. The nominally significant associations found in this study may even suggest that in the case of non-verbal cognitive ability, beneficial associations with homozygosity at specific loci might outweigh the negative effects of genome-wide inbreeding and that the relationship between inbreeding and cognitive ability may be more complicated than previously thought.

European Journal of Human Genetics , (17 July 2013) | doi:10.1038/ejhg.2013.155

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Robert A Power et al.

The consequence of reduced cognitive ability from inbreeding has long been investigated, mainly restricted to cousin–cousin marriages. Molecular genetic techniques now allow us to test the relationship between increased ancestral inbreeding and cognitive ability in a population of traditionally unrelated individuals. In a representative UK sample of 2329 individuals, we used genome-wide SNP data to estimate the percentage of the genome covered by runs of homozygous SNPs (ROH). This was tested for association with general cognitive ability, as well as measures of verbal and non-verbal ability. Further, association was tested between these traits and specific ROH. Burden of ROH was not associated with cognitive ability after correction for multiple testing, although burden of ROH was nominally associated with increased non-verbal cognitive ability (P=0.03). Moreover, although no individual ROH was significantly associated with cognitive ability, there was a significant bias towards increased cognitive ability in carriers of ROH (P=0.002). A potential explanation for these results is increased positive assortative mating in spouses with higher cognitive ability, although we found no evidence in support of this hypothesis in a separate sample. Reduced minor allele frequency across the genome was associated with higher cognitive ability, which could contribute to an apparent increase in ROH. This may reflect minor alleles being more likely to be deleterious.

Link

Population structure in the Netherlands

The three PCs are color-coded in panels b,c,d.

European Journal of Human Genetics , (27 March 2013) | doi:10.1038/ejhg.2013.48

Population structure, migration, and diversifying selection in the Netherlands

Abdel Abdellaoui et al.

Genetic variation in a population can be summarized through principal component analysis (PCA) on genome-wide data. PCs derived from such analyses are valuable for genetic association studies, where they can correct for population stratification. We investigated how to capture the genetic population structure in a well-characterized sample from the Netherlands and in a worldwide data set and examined whether (1) removing long-range linkage disequilibrium (LD) regions and LD-based SNP pruning significantly improves correlations between PCs and geography and (2) whether genetic differentiation may have been influenced by migration and/or selection. In the Netherlands, three PCs showed significant correlations with geography, distinguishing between: (1) North and South; (2) East and West; and (3) the middle-band and the rest of the country. The third PC only emerged with minimized LD, which also significantly increased correlations with geography for the other two PCs. In addition to geography, the Dutch North–South PC showed correlations with genome-wide homozygosity (r=0.245), which may reflect a serial-founder effect due to northwards migration, and also with height (♂: r=0.142, ♀: r=0.153). The divergence between subpopulations identified by PCs is partly driven by selection pressures. The first three PCs showed significant signals for diversifying selection (545 SNPs - the majority within 184 genes). The strongest signal was observed between North and South for the functional SNP in HERC2 that determines human blue/brown eye color. Thus, this study demonstrates how to increase ancestry signals in a relatively homogeneous population and how those signals can reveal evolutionary history.

Link

Estimating heterozygosity from low coverage sequencing data

arXiv:1212.4125 [q-bio.PE]

Estimating heterozygosity from a low-coverage genome sequence, leveraging data from other individuals sequenced at the same sites

Katarzyna Bryc, Nick Patterson, David Reich

High-throughput shotgun sequence data makes it possible in principle to accurately estimate population genetic parameters without confounding by SNP ascertainment bias. One such statistic of interest is the proportion of heterozygous sites within an individual's genome, which is informative about inbreeding and effective population size. However, in many cases, the available sequence data of an individual is limited to low coverage, preventing the confident calling of genotypes necessary to directly count the proportion of heterozygous sites. Here, we present a method for estimating an individual's genome-wide rate of heterozygosity from low-coverage sequence data, without an intermediate step calling genotypes. Our method jointly learns the shared allele distribution between the individual and a panel of other individuals, together with the sequencing error distributions and the reference bias. We show our method works well, first by its performance on simulated sequence data, and secondly on real sequence data where we obtain estimates using low coverage data consistent with those from higher coverage. We apply our method to obtain estimates of the rate of heterozygosity for 11 humans from diverse world-wide populations, and through this analysis reveal the complex dependency of local sequencing coverage on the true underlying heterozygosity, which complicates the estimation of heterozygosity from sequence data. We show filters can correct for the confounding by sequencing depth. We find in practice that ratios of heterozygosity are more interpretable than absolute estimates, and show that we obtain excellent conformity of ratios of heterozygosity with previous estimates from higher coverage data.

Link

Runs of homozygosity, short and long

Runs of homozygosity (ROHs) occur when an individual inherits the same version of a genomic region from both his parents. They can be fairly short, or quite long; in the latter case, they are usually the result of inbreeding, especially marriages between close relatives, because recombination did not have enough time to break down a long segment that has been inherited from the same ancestor via both parents.

Shorter runs of homozygosity have the potential of informing us about population history. Populations that go through a bottleneck go through a patch of intense inbreeding, that will result in long ROHs as in the previous case. But, as time passes on, and provided that alternative version of genomic regions survived the bottleneck, recombination breaks down these long ROHs and the individual becomes a patchwork of homozygous and heterozygous regions.

Mutation, too, disturbs ROHs by introducing new variants into the population. New mutations appear more often in populations with a larger number of breeding individuals. Finally, admixture may disturb ROHs as well. Admixed individuals are more likely to inherent divergent regions of DNA throughout their genome, and hence be less homozygous.

The data presented in this paper seems to point to the fact that long ROHs are observed in populations where marriages between close kin are common. The authors split -for each population separately- ROHs into different classes based on length, and they observe that the short class of ROHs is shorter in Africans than non-Africans.

The implications of this are not explored, but such a pattern is consistent both with an Out-of-Africa bottleneck, as well as old admixture events within a structured African population. Unlike recent admixture events that result in long heterozygous tracts, old admixture events result in extraneous segments of DNA that become ever-reduced in size due to recombination. At the limit, admixture is equivalent to an excess of mutation, and it is very difficult to distinguish between an excess of apparent mutation that has arisen in a larger breeding population vs. one that has arisen because very divergent populations admixed in the very deep past.

Razib also covers this.

The American Journal of Human Genetics, Volume 91, Issue 2, 275-292, 10 August 2012

Genomic Patterns of Homozygosity in Worldwide Human Populations

Trevor J. Pemberton et al.

Genome-wide patterns of homozygosity runs and their variation across individuals provide a valuable and often untapped resource for studying human genetic diversity and evolutionary history. Using genotype data at 577,489 autosomal SNPs, we employed a likelihood-based approach to identify runs of homozygosity (ROH) in 1,839 individuals representing 64 worldwide populations, classifying them by length into three classes—short, intermediate, and long—with a model-based clustering algorithm. For each class, the number and total length of ROH per individual show considerable variation across individuals and populations. The total lengths of short and intermediate ROH per individual increase with the distance of a population from East Africa, in agreement with similar patterns previously observed for locus-wise homozygosity and linkage disequilibrium. By contrast, total lengths of long ROH show large interindividual variations that probably reflect recent inbreeding patterns, with higher values occurring more often in populations with known high frequencies of consanguineous unions. Across the genome, distributions of ROH are not uniform, and they have distinctive continental patterns. ROH frequencies across the genome are correlated with local genomic variables such as recombination rate, as well as with signals of recent positive selection. In addition, long ROH are more frequent in genomic regions harboring genes associated with autosomal-dominant diseases than in regions not implicated in Mendelian diseases. These results provide insight into the way in which homozygosity patterns are produced, and they generate baseline homozygosity patterns that can be used to aid homozygosity mapping of genes associated with recessive diseases.

Link

Should incestuous marriages be allowed?

German incest couple lose European Court case

A brother and sister from Germany who had an incestuous relationship, arguing they had the right to a family life, have lost their European court case.

Patrick Stuebing and Susan Karolewski had four children together, two of whom are described as disabled.

The European Court of Human Rights said Germany was entitled to ban incest.

Stuebing, who was convicted of incest and spent three years in prison, did not meet his natural sister until he tracked down his family as an adult.

He had been adopted as a child and only made contact with his natural relatives in his 20s.

The siblings grew close after their mother died.

Three of their four children are now looked after in care.

The couple insist that their love is no different to any other.

Of course, I applaud the decision of the ECHR, but I take a rather different view on the justification of it.

Regulation of marriage is central to the moral and legal codes of almost all human societies. Different societies limit marriage in diverse ways:

1. Age (young people are generally disallowed from marrying, and early marriage has become legally and socially more difficult in much of the world)
2. Sex (people of opposing sex may marry, although recently some societies have allowed same-sex marriage)
3. Number (some societies demand exclusivity, while others allow for husbands to marry multiple wives, or more commonly for women to take multiple husbands)
4. Relation (marriage between close relatives are often prohibited, (almost) universally for parent-offspring or sibling marriage; on the other hand cousin or uncle-niece marriage is prohibited in some societies, or encouraged in others)
5. Race (there were formerly legal prohibitions of inter-racial marriage, and there are societies in which such marriages are often frowned upon still)
6. Religion (some belief systems do not require that partners be of the same religion, while others do so)
7. Social status (marriage across class or caste lines was formerly prohibited either legally or socially, and is still often uncommon)
8. Former marriage status (divorce and re-marriage sometimes prohibited, provisions for widowhood, etc.)

It is clear that society has deemed the institution of marriage to be an important one, and this is why it has imposed so many legal and social rules upon it. In recent years, the trend has been one towards laissez-faire in the regulation of human affairs. This has been most evident in the case of same sex "marriage", whose advocates actively frame the question in terms of the "rights" of consenting persons.

If the matter is that of constitutional or other "rights", then the state oversteps its role in preventing two consenting persons from entering into the institution of marriage. Those who hold to this view, however, often promote the "right" to marriage of their own particular interest group (mostly of the homosexual community), but downplay similar claims to marriage of other groups (e.g., prohibition against polygamy, incest, young marriage, etc.)

There is a different line of thought, which frames the question of marriage in utilitarian terms. Marriage is seen as promoting child-rearing, family stability, engendering close social ties, and promoting the well-being and happiness of individuals. Again, those who hold to this view propose that their particular form of marriage is useful, while opposing certain forms of marriage for its adverse effects (e.g., the costs associated with invalids born of incestuous marriages, or increased expenditure when economic benefits are extended to new forms of marriage).

When the moral compass of a society atrophies, then its most fundamental institutions become the playing ground of lawyers and economists. Of course, this is a perfectly valid point of view -if one thinks that lawyers and economists, rather than ethicists and priests- make the better judges of what is to be allowed.

Proponents of the modern, secular, and democratic way of doing things will argue that it is an improvement for the rules to be made in the context of Constitutional Law, Democratic Choice, and Economic Expediency.

But, we must not forget that their chosen framework of accepted behavior is not as sure-footed as they may think, because what else is Democracy than the idea that the many are right over the few? What else is adherence to a Constitution than the faith in the idea that what men voted for generations ago should guide the behavior of the living? And, what else is Economics, other than the idea that human prosperity revolves around the maximization of some economic quantity?

To conclude: questions such as "should incestuous marriage be allowed?" force us all to think about who decides the "should."

Craster's daughters

The second season of Game of Thrones has started and the series has become the topic of some fun discussion, I thought I'd give my €0.02 on the topic of genetic improbabilities.

(A warning: I have only read the first book, so please refrain from spoiling in the comments. Also, this post contains a minor spoiler about the first episode of season 2)

One of the good things about fiction is that it brings up interesting probabilities that would not often come up in the real world. In the first episode of Season 2, we are introduced to Craster, a character who lives north of the Wall. The interesting thing about Craster is that he practices a combination of incest and infanticide: he exposes his male offspring and weds his daughters, repeating the cycle. Let's examine whether or not this scenario is plausible:

• In the first generation, Craster would have a 50% coefficient of relatedness with his daughters.
• In the second generation, this would increase to 75%. In the third, this would be 87.5%, etc.

What is interesting is that their autozygosity would also increase across the generations.

In the first generation, at a random locus the probability that both copies have been inherited from the same ancestor is some random number corresponding to the probability of identity-by-descent in the general population.

In the second generation, at half the loci there is a 50-50 chance that the same allele will be inherited from Craster, hence the grand-daughters will be autozygous across at least 25% of the genome. This means that they will be homozygous for about a quarter of Craster's deleterious genetic load.

When we first see Craster, he seems to have quite a few "wives", so my guess is that this has been going on for 2-3 generations at least, which seems plausible given the early age of marriage in a quasi-medieval world.

However, given the severe abnormalities observed in children of father-daughter incest it will become increasingly difficult for Craster to obtain viable offspring through this practice. Many of his children would be aborted, die, or be severely incapacitated.

In order to increase his harem's size (as he seems to be doing) he would need each of his wives to produce 2 daughters for him. This translates to an average of 4 offspring per daughter (since 2 boys will also be born, on average, and exposed).

But, due to high levels of autozygosity, many of Craster's offspring would not be viable; hence, each wife must undergo a very large number of pregnancies. And, given that each wife is heavily inbred herself, she is less likely to survive many pregnancies, especially since there's no ob/gyn north of the Wall.

In conclusion, the tale of "Craster and his Wives" does seem to fit well in a work of fantasy...

Marital distance and height of children

AJPA DOI: 10.1002/ajpa.21482

Isolation by distance between spouses and its effect on children's growth in height

Sławomir Kozieł et al.

Heterosis is thought to be an important contributor to human growth and development. Marital distance (distance between parental birthplaces) is commonly considered as a factor favoring the occurrence of heterosis and can be used as a proximate measure of its level. The aim of this study is to assess the net effect of expected heterosis resulting from marital migration on the height of offspring, controlling for midparental height and socioeconomic status (SES). Height measurements on 2,675 boys and 2,603 girls ages 6 to 18 years from Ostrowiec Świętokrzyski, Poland were analyzed along with sociodemographic data from their parents. Midparental height was calculated as the average of the reported heights of the parents. Analyses revealed that marital distance, midparental height, and SES had a significant effect on height in boys and girls. The net effect of marital distance was much more marked in boys than girls, whereas other factors showed comparable effects. Marital distance appears to be an independent and important factor influencing the height of offspring. According to the “isolation by distance” hypothesis, greater distance between parental birthplaces may increase heterozygosity, potentially promoting heterosis. We propose that these conditions may result in reduced metabolic costs of growth among the heterozygous individuals.

Link

Genomic runs of homozygosity in worldwide populations (Kirin et al. 2010)

This is a very interesting paper about the global distribution of runs of homozygosity. Such runs are typical of recently inbred individuals (who have a greater chance of inheriting the same chunk of DNA from their related parents), but also occur because of population history (populations that today number in the millions are descended from a much smaller of ancestors, so even if one's parents aren't "relatives" in the genealogical sense, they, nonetheless contain chunks of identical DNA).

"Old" inbreeding manifests itself in small chunks, as DNA chunks of ancestors get cut into ever finer pieces across the generations, while recently inbred individuals may have very long chunks.

Oceanians and Native Americans, for example, who are descended from relatively few founders because of the bottlenecks associated with crossing the Beringian/maritime voyages have an excess of short runs of homozygosity, but Native Americans also have long ones, suggestive of recent consanguinity.

Raw data can be found in the supplement.

PLoS ONE 5(11): e13996. doi:10.1371/journal.pone.0013996

Genomic Runs of Homozygosity Record Population History and Consanguinity

Mirna Kirin et al.

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (Ne), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental Ne (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.

Link

Population structure in Ireland and Britain (O'Dushlaine et al. 2010)

From the paper:

Eigensoft PCA analysis across all seven of our European and European-ancestry populations broadly identified four sub-groups consisting of (i) Bulgarian, (ii) Portuguese, (iii) Swedish and (iv) Irish/British/Utah populations (see Figure 1a, Supplementary Figure S1). The first two principal components (PCs) separate out northern from southern, and western from eastern European ancestry, respectively. The Europe-wide PCA analysis positions the Scottish population (Aberdeen) intermediate between the Irish and English populations. We further explored this observation by restricting our PC analysis to residents of Ireland, Scotland (Aberdeen) and south/southeast England (Figure 1b, Supplementary Figure S1). This analysis confirms the observation that the Scottish population is intermediate between the Irish and English cohorts on the first principal component(this time dividing west from east). Although more subtle, the Scottish cohort is also shifted slightly from the other two on PC2.

The distinction between Britons and Swedes was also noted in an earlier study. It's nice to see Bulgarians and Portuguese sampled, as they have been rather neglected in genomic studies, but, unfortunately none of their neighbors or any other intermediate populations were included, which is understandable as the study focused on British Isles populations. Bulgarians and Portuguese served as "anchor points" to re-create the well-known correlation of the first two PCs of European genetic variation with longitude/latitude.

The intermediate position of Scottish populations relative to the Irish and English is not surprising, given the Gaelic connection between Scotland and Ireland.

The paper also has haplotype diversity data that can be compared with those recently published by Auton et al.

The authors observe:

In summary, our results illustrate a subtle genetic structure across Britain and Ireland in the context of the comparatively homogenous nature of the European genetic pool. We have observed slightly elevated levels of LD and genome-wide homozygosity in Ireland and Sweden compared with neighbouring British and European populations, although these levels do not approach those of traditional population isolates. Similarly, we have illustrated a decrease in HD in Britain and Ireland, more so in Scotland and Ireland than in England.

Finally, the authors present results of frappe analysis (Figure S2):


At K=2 we see a distinction between northern and southern Europeans.

At K=3 a distinction between British Isles and Sweden appears. The absence of the Western European component in Bulgarians is noteworthy and expected.

At K=4 the Bulgarian component is identified.

At K=5 a Portuguese component is identified.

British Isles populations are dominated by the "Northwestern" green component with variable "Scandinavian" white (which is higher in England as expected) and both "Iberian" and "Balkan" minority elements.

European Journal of Human Genetics doi: 10.1038/ejhg.2010.87

Population structure and genome-wide patterns of variation in Ireland and Britain

Colm T O'Dushlaine et al.

Abstract

Located off the northwestern coast of the European mainland, Britain and Ireland were among the last regions of Europe to be colonized by modern humans after the last glacial maximum. Further, the geographical location of Britain, and in particular of Ireland, is such that the impact of historical migration has been minimal. Genetic diversity studies applying the Y chromosome and mitochondrial systems have indicated reduced diversity and an increased population structure across Britain and Ireland relative to the European mainland. Such characteristics would have implications for genetic mapping studies of complex disease. We set out to further our understanding of the genetic architecture of the region from the perspective of (i) population structure, (ii) linkage disequilibrium (LD), (iii) homozygosity and (iv) haplotype diversity (HD). Analysis was conducted on 3654 individuals from Ireland, Britain (with regional sampling in Scotland), Bulgaria, Portugal, Sweden and the Utah HapMap collection. Our results indicate a subtle but clear genetic structure across Britain and Ireland, although levels of structure were reduced in comparison with average cross-European structure. We observed slightly elevated levels of LD and homozygosity in the Irish population compared with neighbouring European populations. We also report on a cline of HD across Europe with greatest levels in southern populations and lowest levels in Ireland and Scotland. These results are consistent with our understanding of the population history of Europe and promote Ireland and Scotland as relatively homogenous resources for genetic mapping of rare variants.

Link

Are mixed-race people more attractive?

This paper has received some attention in the media, so it is worthwhile to consider its thesis: that great attractiveness of mixed-race people is due to genetic heterosis.

From the paper:

Facial images were harvested from the social networking website facebook.com. These were collected according to social groups that the people submitting the images belonged to. People who were members of groups making reference to being of mixed race [eg ``mixed race and proud of it''](1) formed a mixed-race group (N . 483). People who were members of groups making reference to groups who were from geographical regions of the UK with minimal ethnic minorities (eg ``Cornish and proud of it'') formed a white group (N . 368). People who were members of groups that made reference to being Black and living in the UK (eg ``Black and brum'') or made reference to coming from parts of Africa (eg ``Gambian and proud'') formed a black group (N . 354).

...

Twenty white psychology students rated each face on its attractiveness on a 9-point scale (5 being of average attractiveness).

Before we consider the "Why" of the paper's title, it is worthwhile to consider whether the thesis itself "mixed-race people are perceived as more attractive" is supported by the evidence. I can think of several alternative explanations for the evidence:

• There is no reason to think that "mixed-race" people represent black-white mixes. In the British context, "mixed-race" may also include white-South Asian or white-East Asian people.
• There is no reason to think that white people from less cosmopolitan areas are equally attractive to white people from big cities. It's reasonable to assume that attractive people thrive in regions of high population density, since attractiveness is a social advantage: you will probably find more "hot" models, actors, PR people, waitresses, salesgirls, etc. in London than you will in Cornwall.
• There is no reason to think that people of average attractiveness (for their respective races) mate to produce mixed-race offspring. Interracial marriage is not the norm (it occurs at a far lower rating than random mating would predict), thus there appears to be a real psychological impediment to the practice. It is not unreasonable to postulate that people are willing to mate interracially for a higher-than-average member of a different race, with the greater attractiveness serving to overcome this obstacle. In any case, the assumption that random whites and blacks mate to produce interracial offspring is not obvious.
• There is no reason to think that people who join mixed-race groups on facebook are good representatives of mixed-race people in general. Non-normative individuals may have a positive, neutral, or negative attitude towards their ancestry, and it is reasonable that "happy" mixed-race people may be more likely to advertise the fact than "non-happy" ones, and that more attractive mixed-race people (representing more harmonious combinations) may be more likely to belong to the first category.
• Finally, there is no reason to think that people who are of mixed-race have the same age as non-mixed people. Race mixing is on the rise both due to immigration and to changing societal norms, so there is probably a negative correlation between racial admixture and age. Thus, the finding of this study may be simply an artifact of the higher average age of the unmixed vs. the mixed groups.

Thus, I don't really think there is any reason to seek the "why" of a non-evident fact. But, it is interesting to consider the explanation for the supposed greater attractiveness of mixed-race people: genetic heterosis. The paper really offers no new evidence that heterosis has an effect on attractiveness.

It would be worthwhile to do a comprehensive study of race and attractiveness. Thankfully, we now possess reasonable genetic estimators of racial admixture and heterozygosity; hopefully someone will have the funds and will to use them.

Nonetheless the paper is useful because it reveals a real effect: what the explanation for this effect is remains to be seen.

Perception 39(1) 136 – 138

Why are mixed-race people perceived as more attractive?

Michael B Lewis

Abstract

Previous, small scale, studies have suggested that people of mixed race are perceived as being more attractive than non-mixed-race people. Here, it is suggested that the reason for this is the genetic process of heterosis or hybrid vigour (ie cross-bred offspring have greater genetic fitness than pure-bred offspring). A random sample of 1205 black, white, and mixed-race faces was collected. These faces were then rated for their perceived attractiveness. There was a small but highly significant effect, with mixed-race faces, on average, being perceived as more attractive. This result is seen as a perceptual demonstration of heterosis in humans—a biological process that may have implications far beyond just attractiveness.

Link

Complete Khoisan and Bantu genomes

The number of published complete genomes is starting to grow exponentially it seems. Pretty soon, I'm guessing, once most major groups are covered by at least one individual, they will cease to be paper-worthy, and we will move on to the era of full-genome population studies.

One of the published individuals is Desmond Tutu, so I am adding this to the Famous DNA label as well.

From the paper:

In the 117 megabases (Mb) of sequenced exome-containing intervals, the average rate of nucleotide differences between a pair of the Bushmen was 1.2 per kilobase, compared to an average of 1.0 per kilobase differing between a European and Asian individual.

It's striking that two Bushmen are more different from each other than a European and an Asian are. This is in agreement with the idea that Bushmen have a substantial Palaeoafrican genomic component, while Eurasians and most other Africans emerged from a younger population flowering within the species, which I have termed "Afrasian". Eurasians are descended from these (presumably East African "Afrasians"), as are most Africans, but with varying degrees of intermixture with other (non-"Afrasian") groups of humans that lived in the continent from times immemorial at the time of the Out-of-Africa (and "Deeper-into-Africa") expansions.

From the paper, number of SNPs shared:

On the right we see some interesting facts for three individuals (Bushman, KB1; Chinese: YH; European-American: J.C. Venter). 2-way sharing between individuals is roughly in the order of ~500. The Bushman has twice as many "private" variation as the Eurasians, consistent with the ancient basal position in the human family.

From the paper:

The large number of novel SNPs raises concerns regarding the ability of current genotyping arrays to capture effectively the true extent of genetic diversity and haplotype structure represented in southern Africa. Assessing percentage heterozygosity for 1,105,569 autosomal SNPs using current-content Illumina arrays, we were surprised to find lower heterozygosity in KB1 compared to a region-matched European control (Supplementary Data and Supplementary Fig. 3a, b), because it is well known that genetic diversity is highest in Africa. However, analysis of whole-genome sequencing data for KB1 and ABT revealed high percentages of heterozygous SNPs (59% and 60%, respectively), as expected. This discrepancy underscores the inadequacy of current SNP arrays for analysing southern African populations.

This is not very surprising: SNPs used in microarrays have not been discovered in Bushmen, so by testing for heterozygosity in Bushmen using them, you actually underestimate it. By not including Bushmen in the SNP-discovery process you implicitly assume non-variability (hence "no SNP") at sites where Bushmen (but not other humans) are variable.

With whole-genome sequencing we are able to see that Bushmen are indeed highly heterozygous. This should serve as a warning for making too much of patterns of heterozygosity from microarray genotype data, even the latest ~1M ones.

The PCA is also interesting as it points out the familiar differentiation between Europeans-African farmers-Bushmen at the top and Bushmen-West-South Africans at the bottom):

NB: The paper is freely available to non-subscribers, so you can go ahead and read it in full.

Nature doi:10.1038/nature08795

Complete Khoisan and Bantu genomes from southern Africa

Stephan C. Schuster et al.

Abstract

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial1 and small sets of nuclear markers2 have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans1, 3. However, until now, fully sequenced human genomes have been limited to recently diverged populations4, 5, 6, 7, 8. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

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45 SNP universal genetic identification

Forensic geneticists currently use the highly polymorphic CODIS microsatellite markers for DNA sample identification. This paper shows that a unique DNA id for a human can be achieved by a panel of 45 SNPs.

Human Genetics doi:10.1007/s00439-009-0771-1

SNPs for a universal individual identification panel

Andrew J. Pakstis et al.

Abstract

An efficient method to uniquely identify every individual would have value in quality control and sample tracking of large collections of cell lines or DNA as is now often the case with whole genome association studies. Such a method would also be useful in forensics. SNPs represent the best markers for such purposes. We have developed a globally applicable resource of 92 SNPs for individual identification (IISNPs) with extremely low probabilities of any two unrelated individuals from anywhere in the world having identical genotypes. The SNPs were identified by screening over 500 likely/candidate SNPs on samples of 44 populations representing the major regions of the world. All 92 IISNPs have an average heterozygosity >0.4 and the F _st values are all less than 0.06 on our 44 populations making these a universally applicable panel irrespective of ethnicity or ancestry. No significant linkage disequilibrium (LD) occurs for all unique pairings of 86 of the 92 IISNPs (median LD = 0.011) in all of the 44 populations. The remaining 6 IISNPs show strong LD in most of the 44 populations for a small subset (7) of the unique pairings in which they occur due to close linkage. 45 of the 86 SNPs are spread across the 22 human autosomes and show very loose or no genetic linkage with each other. These 45 IISNPs constitute an excellent panel for individual identification including paternity testing with associated probabilities of individual genotypes less than 10⁻¹⁵, smaller than achieved with the current panels of forensic markers. This panel also improves on an interim panel of 40 IISNPs previously identified using 40 population samples. The unlinked status of the subset of 45 SNPs we have identified also makes them useful for situations involving close biological relationships. Comparisons with random sets of SNPs illustrate the greater discriminating power, efficiency, and more universal applicability of this IISNP panel to populations around the world. The full set of 86 IISNPs that do not show LD can be used to provide even smaller genotype match probabilities in the range of 10⁻³¹–10⁻³⁵ based on the 44 population samples studied.

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Two bottlenecks shaped human genetic diversity

Proceedings of the Royal Society B doi:10.1098/rspb.2009.1473

Evidence that two main bottleneck events shaped modern human genetic diversity

W. Amos and J. I. Hoffman

Abstract

There is a strong consensus that modern humans originated in Africa and moved out to colonize the world approximately 50 000 years ago. During the process of expansion, variability was lost, creating a linear gradient of decreasing diversity with increasing distance from Africa. However, the exact way in which this loss occurred remains somewhat unclear: did it involve one, a few or a continuous series of population bottlenecks? We addressed this by analysing a large published dataset of 783 microsatellite loci genotyped in 53 worldwide populations, using the program ‘Bottleneck’. Immediately following a sharp population decline, rare alleles are lost faster than heterozygosity, creating a transient excess of heterozygosity relative to allele number, a feature that is used by Bottleneck to infer historical events. We find evidence of two primary events, one ‘out of Africa’ and one placed around the Bering Strait, where an ancient land bridge allowed passage into the Americas. These findings agree well with the regions of the world where the largest founder events might have been expected, but contrast with the apparently smooth gradient of variability that is revealed when current heterozygosity is plotted against distance from Africa.

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Is Homo sapiens polytypic?

An interesting paper worth reading, which considers the idea that Homo sapiens can be subdivided to subspecies against two diametrically opposite ideas, namely (i) that there are no human subspecies, and (ii) that human taxonomic differences warrant the rank of species. The author rejects (i) on the grounds that Homo sapiens exhibit higher levels of diversity (in terms of heterozygosity and Fst) compared to species where subspecies are recognized. I had not heard of (ii) argued recently, but Woodley cites Fuerle as a recent supporter, offering the following criticism:

FST reflects the relative amount of total genetic differentiation between populations, however different measures of genetic distance involving mtDNA and autosomal loci are simply inappropriate for the purposes of inter-specific comparison as the different genes involved will have been subject to markedly different selection pressures and are therefore not likely to have diverged at the same time [62]. To illustrate this point, this author listed alternative estimates of the distance between the gorilla species and the common chimpanzee and bonobo, based on various nuclear loci and autosomal DNA. The much higher numbers reflect the extreme variation that can be expected when different genes are considered. Fuerle’s presentation of the data is also problematic for another reason, namely he makes no mention of the current debates surrounding gorilla and chimpanzee/bonobo taxonomy; as new research on these taxa regularly generates novel and in some cases wildly variable estimates of genetic distance between these primates, and there is even some debate over whether the eastern and western gorillas are separate species [60].

Curnoe and Thorne have estimated that periods of around two million years were required for the production of sufficient genetic distances to represent speciation within the human ancestral lineage [56]. This indicates that the genetic distances between the races are too small to warrant differentiation at the level of biological species, as the evolution of racial variation within H. sapiens started to occur only 60,000 years ago, when the ancestors of modern humans first left Africa.

Personally I think that the evidence is clear that human races or subspecies exist, but the discovery that geographic differentiation exists at the level of races, ethnic groups, sub-ethnic groups, and that even villages can be subdivided into geographically distinguishable clusters, make renewed effort into formalizing taxonomy at the sub-species level an especially worthwhile endeavor.

Medical Hypotheses doi:10.1016/j.mehy.2009.07.046

Is Homo sapiens polytypic? Human taxonomic diversity and its implications

Michael A. Woodley

Abstract

The term race is a traditional synonym for subspecies, however it is frequently asserted that Homo sapiens is monotypic and that what are termed races are nothing more than biological illusions. In this manuscript a case is made for the hypothesis that H. sapiens is polytypic, and in this way is no different from other species exhibiting similar levels of genetic and morphological diversity. First it is demonstrated that the four major definitions of race/subspecies can be shown to be synonymous within the context of the framework of race as a correlation structure of traits. Next the issue of taxonomic classification is considered where it is demonstrated that H. sapiens possesses high levels morphological diversity, genetic heterozygosity and differentiation (FST) compared to many species that are acknowledged to be polytypic with respect to subspecies. Racial variation is then evaluated in light of the phylogenetic species concept, where it is suggested that the least inclusive monophyletic units exist below the level of species within H. sapiens indicating the existence of a number of potential human phylogenetic species; and the biological species concept, where it is determined that racial variation is too small to represent differentiation at the level of biological species. Finally the implications of this are discussed in the context of anthropology where an accurate picture of the sequence and timing of events during the evolution of human taxa are required for a complete picture of human evolution, and medicine, where a greater appreciation of the role played by human taxonomic differences in disease susceptibility and treatment responsiveness will save lives in the future.

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Coalescent-based serial founder model of migration outward from Africa (DeGiorgio et al. 2009)

Proc Natl Acad Sci U S A. 2009 Aug 17. [Epub ahead of print]

Out of Africa: Modern Human Origins Special Feature: Explaining worldwide patterns of human genetic variation using a coalescent-based serial founder model of migration outward from Africa.

Degiorgio M, Jakobsson M, Rosenberg NA.

Studies of worldwide human variation have discovered three trends in summary statistics as a function of increasing geographic distance from East Africa: a decrease in heterozygosity, an increase in linkage disequilibrium (LD), and a decrease in the slope of the ancestral allele frequency spectrum. Forward simulations of unlinked loci have shown that the decline in heterozygosity can be described by a serial founder model, in which populations migrate outward from Africa through a process where each of a series of populations is formed from a subset of the previous population in the outward expansion. Here, we extend this approach by developing a retrospective coalescent-based serial founder model that incorporates linked loci. Our model both recovers the observed decline in heterozygosity with increasing distance from Africa and produces the patterns observed in LD and the ancestral allele frequency spectrum. Surprisingly, although migration between neighboring populations and limited admixture between modern and archaic humans can be accommodated in the model while continuing to explain the three trends, a competing model in which a wave of outward modern human migration expands into a series of preexisting archaic populations produces nearly opposite patterns to those observed in the data. We conclude by developing a simpler model to illustrate that the feature that permits the serial founder model but not the archaic persistence model to explain the three trends observed with increasing distance from Africa is its incorporation of a cumulative effect of genetic drift as humans colonized the world.

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Genetic diversity and every-day health in humans

From the paper:

These results provide some support for an association between genetic diversity and a measure of general, everyday health in humans. We found a small, but significant, effect of nonMHC genetic diversity, measured as standardized mean-d2, on health. Individuals with greater nonMHC-d2 reported significantly fewer symptoms over a four-month period than less diverse individuals, with nonMHC-d2 accounting for 3% of the variance in health. This relationship suggests that the previously observed male preferences for the faces of females with high levels of nonMHC-d2 would be adaptive for obtaining a healthier mate [46].

PLoS ONE doi:10.1371/journal.pone.0006391

Does Genetic Diversity Predict Health in Humans?

Hanne C. Lie et al.

Abstract

Genetic diversity, especially at genes important for immune functioning within the Major Histocompatibility Complex (MHC), has been associated with fitness-related traits, including disease resistance, in many species. Recently, genetic diversity has been associated with mate preferences in humans. Here we asked whether these preferences are adaptive in terms of obtaining healthier mates. We investigated whether genetic diversity (heterozygosity and standardized mean d2) at MHC and nonMHC microsatellite loci, predicted health in 153 individuals. Individuals with greater allelic diversity (d2) at nonMHC loci and at one MHC locus, linked to HLA-DRB1, reported fewer symptoms over a four-month period than individuals with lower d2. In contrast, there were no associations between MHC or nonMHC heterozygosity and health. NonMHC-d2 has previously been found to predict male preferences for female faces. Thus, the current findings suggest that nonMHC diversity may play a role in both natural and sexual selection acting on human populations.

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Major Histocompatibility Complex (MHC) diversity and human facial attractiveness

Previous research has shown that faces of MHC heterozygous males are judged more attractive. The new study confirms the findings of the earlier one, by finding a preference of females to MHC heterozygous males, with MHC heterozygosity being predictive of facial averageness in both sexes.

Evolution Volume 62 Issue 10, Pages 2473 - 2486

GENETIC DIVERSITY REVEALED IN HUMAN FACES

Hanne C. Lie et al.

Abstract

From an evolutionary perspective, human facial attractiveness is proposed to signal mate quality. Using a novel approach to the study of the genetic basis of human preferences for facial features, we investigated whether attractiveness signals mate quality in terms of genetic diversity. Genetic diversity in general has been linked to fitness and reproductive success, and genetic diversity within the major histocompatibility complex (MHC) has been linked to immunocompetence and mate preferences. We asked whether any preference for genetic diversity is specific to MHC diversity or reflects a more general preference for overall genetic diversity. We photographed and genotyped 160 participants using microsatellite markers situated within and outside the MHC, and calculated two measures of genetic diversity: mean heterozygosity and standardized mean d2. Our results suggest a special role for the MHC in female preferences for male faces. MHC heterozygosity positively predicted male attractiveness, and specifically facial averageness, with averageness mediating the MHC-attractiveness relationship. For females, standardized mean d2 at non-MHC loci predicted facial symmetry. Thus, attractive facial characteristics appear to provide visual cues to genetic quality in both males and females, supporting the view that face preferences have been shaped by selection pressures to identify high-quality mates.

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Heterozygosity and heart-related quantitative traits

Annals of Human Genetics doi:10.1111/j.1469-1809.2009.00514.x

Association between SNP Heterozygosity and Quantitative Traits in the Framingham Heart Study

Didahally R. Govindaraju et al.

Abstract

Associations between multilocus heterozygosity and fitness traits, also termed heterozygosity and fitness correlations (HFCs), have been reported in numerous organisms. These studies, in general, indicate a positive relationship between heterozygosity and fitness traits. We studied the association between genome-wide heterozygosity at 706 non-synonymous and synonymous SNPs and 19 quantitative traits, including morphological, biochemical and fitness traits in the Framingham Heart Study. Statistically significant association was found between heterozygosity and systolic and diastolic blood pressures as well as left ventricular diameter and wall thickness. These results suggest that heterozygosity may be associated with traits, such as blood pressure that closely track environmental variations. Balancing selection may be operating in the maintenance of heterozygosity and the major components of blood pressure and hypertension. Genome wide SNP heterozygosity may be used to understand the phenomenon of dominance as well as the evolutionary basis of many quantitative traits in humans.

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MHC-dissimilar mating in Brazil

This seems to parallel previous findings on European Americans.

Opposites attract -- how genetics influences humans to choose their mates

Vienna, Austria: New light has been thrown on how humans choose their partners, a scientist will tell the annual conference of the European Society of Human Genetics today (Monday May 25). Professor Maria da Graça Bicalho, head of the Immunogenetics and Histocompatibility Laboratory at the University of Parana, Brazil, says that her research had shown that people with diverse major histocompatibility complexes (MHCs) were more likely to choose each other as mates than those whose MHCs were similar, and that this was likely to be an evolutionary strategy to ensure healthy reproduction.

Females' preference for MHC dissimilar mates has been shown in many vertebrate species, including humans, and it is also known that MHC influences mating selection by preferences for particular body odours. The Brazilian team has been working in this field since 1998, and decided to investigate mate selection in the Brazilian population, while trying to uncover the biological significance of MHC diversity.

The scientists studied MHC data from 90 married couples, and compared them with 152 randomly-generated control couples. They counted the number of MHC dissimilarities among those who were real couples, and compared them with those in the randomly-generated 'virtual couples'. "If MHC genes did not influence mate selection", says Professor Bicalho, "we would have expected to see similar results from both sets of couples. But we found that the real partners had significantly more MHC dissimilarities than we could have expected to find simply by chance."

Within MHC-dissimilar couples the partners will be genetically different, and such a pattern of mate choice decreases the danger of endogamy (mating among relatives) and increases the genetic variability of offspring. Genetic variability is known to be an advantage for offspring, and the MHC effect could be an evolutionary strategy underlying incest avoidance in humans and also improving the efficiency of the immune system, the scientists say.

The MHC is a large genetic region situated on chromosome 6, and found in most vertebrates. It plays an important role in the immune system and also in reproductive success. Apart from being a large region, it is also an extraordinarily diverse one.

"Although it may be tempting to think that humans choose their partners because of their similarities", says Professor Bicalho, "our research has shown clearly that it is differences that make for successful reproduction, and that the subconscious drive to have healthy children is important when choosing a mate."

The scientists believe that their findings will help understanding of conception, fertility, and gestational failures. Research has already shown that couples with similar MHC genes had longer intervals between births, which could imply early, unperceived miscarriages. "We intend to follow up this work by looking at social and cultural influences as well as biological ones in mate choice, and relating these to the genetic diversity of the extended MHC region", says Professor Bicalho.

"We expect to find that cultural aspects play an important role in mate choice, and certainly do not subscribe to the theory that if a person bears a particular genetic variant it will determine his or her behaviour. But we also think that the unconscious evolutionary aspect of partner choice should not be overlooked. We believe our research shows that this has an important role to play in ensuring healthy reproduction, by helping to ensure that children are born with a strong immune system better able to cope with infection."

I had previously posted some more abstracts from ESHG 2009. Here is the abstract from this study:

New evidences about MHC-based patterns of mate choice

M. Bicalho, J. da Silva, J. M. Magalhães, W. Silva;

Major Histocompatibility Complex (MHC) genes code for cell surface proteins, which plays an important role in immune recognition. In the late 1970s, Yamazaki observed that inbred mice were more likely to mate with partners having MHC dissimilar genes. Females’ preference for MHC dissimilar mates was also observed in other vertebrate species, including humans. It has been shown that MHC influences mating selection mediated by preferences based on body odor. What’s the functional significance of these findings, if some? It was assumed that through olfactory cues MHC-related evolved as a strategy to maximize the offspring MHC heterozygosity. Parents with dissimilar MHCs could provide their offspring with a better chance to ward infections off because their immune system genes are more diverse. MHC genotype might be used to signal relatedness and immune response genotypes through.

We investigated whether husband-wife couples (n=90) obtained from LIGH’s database were more MHC-similar/dissimilar in comparison to random couples generated from the same database (n=55 000) as to collect evidence of MHC influence in MHC-based patterns of mate choice.

The individuals HLA typing (Class I and Class II) was performed by PCR-SSP or PCR-rSSOP using a commercial kit ( One Lambda Inc., Canoga Park. CA, USA).

Our results and comparisons ( p= 0,014) suggest that couples seem to be formed by individuals with less HLA similarity, corroborating the hypothesis that HLA antigens, especially Class I, may influence mate selection and marriages in humans.

Female mice prefer outbred males

BMC Evol Biol. 2009 May 16;9(1):104. [Epub ahead of print]

Females prefer the scent of outbred males: good-genes-as-heterozygosity?

Ilmonen P, Stundner G, Thosz M, Penn DJ.

ABSTRACT: BACKGROUND: There is increasing interest to determine the relative importance of non-additive genetic benefits as opposed to additive ones for the evolution of mating preferences and maintenance of genetic variation in sexual ornaments. The 'good-genes-as-heterozygosity' hypothesis predicts that females should prefer to mate with more heterozygous males to gain more heterozygous (and less inbred) offspring. Heterozygosity increases males' sexual ornamentation, mating success and reproduction success, yet few experiments have tested whether females are preferentially attracted to heterozygous males, and none have tested whether females' own heterozygosity influences their preferences. Outbred females might have the luxury of being more choosey, but on the other hand, inbred females might have more to gain by mating with heterozygous males. We manipulated heterozygosity in wild-derived house mice (Mus musculus musculus) through inbreeding and tested whether the females are more attracted to the scent of outbred versus inbred males, and whether females' own inbreeding status affects their preferences. We also tested whether infecting both inbred and outbred males with Salmonella would magnify females' preferences for outbred males. RESULTS: Females showed a significant preference for outbred males, and this preference was slightly more pronounced among inbred females. We found no evidence that Salmonella infection increased the relative attractiveness of outbred versus inbred males; however, we found no evidence that inbreeding affected males' disease resistance in this study. CONCLUSIONS: Our findings support the idea that females are more attracted to outbred males, and they suggest that such preferences may be stronger among inbred than outbred females, which is consistent with the 'good-genes-as-heterozygosity' hypothesis. It is unclear whether this odour preference reflects females' actual mating preferences, though it suggests that future studies should consider females' as well as males' heterozygosity. Our study has implications for efforts to understand how mate choice can provide genetic benefits without eroding genetic diversity (lek paradox), and also conservation efforts to determine the fitness consequences of inbreeding and the maintenance of genetic diversity in small, inbred populations.

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