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.

Link

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.

Link

Common variants and schizophrenia

Until now, the hunt for the genetic etiology of psychiatric disorders didn't go very well. Three new papers in Nature make some progress by noting that a combination of many genes, especially of the Major Histocompatibility Complex is predictive of schizophrenia and bipolar disorder risk. From the NIH news release:

Three schizophrenia genetics research consortia, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (ISC) and Molecular Genetics of Schizophrenia (MGS) consortia shared their results – making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.

All three studies implicate an area of Chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.

From news.com.au:

As well as pinpointing key immune system mutations, complementary discoveries from each consortium showed clearly that many small genetic variations combine in different ways to increase a person's risk of developing schizophrenia.

"If you look at any individual with schizophrenia no single gene is really strong, but put these genes together and you get a meaningful influence," Dr Cairns said.

From the deCODE news release:

"Genetics offers a unique window for better understanding diseases like schizophrenia because the brain and cognition are so little understood and so difficult to study. Discoveries such as these are crucial for teasing out the biology of the disease and making it possible for us to begin to develop drugs targeting the underlying causes and not just the symptoms of the disease. One of the reasons this study was so successful is its unprecendented size. Pooling our resources has yielded spectacular results, which is what the participants from three continents hoped for. At the same time, this study underscores the fact that rare variants may well carry a significant part of the genetic risk of schizophrenia, so our next task is to use the ever more affordable sequencing technologies to find more of them," said Kari Stefansson, CEO of deCODE and corresponding author on the paper.

In the first phase of the study, the deCODE-led SGENE consortium conducted a genome-wide scan of more than 300,000 SNPs in a total of 17,000 patients and controls from England, Finland, Germany, Iceland, Italy and Scotland. The 1500 SNPs with the best signal were then analyzed in 11,000 patients and controls from the International Schizophrenia Consortium (ISC) and the European-American portion of the Molecular Genetics of Schizophrenia studies (MGS). Twenty-five SNPs with strong suggestive correlation were then followed up in more than 20,000 patients and controls from the Netherlands, Denmark, Germany, Hungary, Norway, Russia, Finland and Spain. Bringing together the results of different consortia established he association between the the total of seven markers on chromosomes 6, 11, and 18 with increased risk of schizophrenia.

So, while these three studies are a vindication of sorts for common variants, the greater part of the risk remains to be found in rare variants that are not captured by the 300K SNPs or so that were genotyped. But, by any means, this is a significant victory in the search for the hidden heritability.

From the Stanford release:

Using commercially available "SNP chips" designed to detect those more-common variants, the investigators looked for differences between the DNA of people with schizophrenia versus the DNA of those without the disease. The scientists required that such differences achieve "genome-wide statistical significance." Here's why: If you flip a million coins, one at a time, you're going to see all kinds of seemingly miraculous events — say, 15 heads in a row — that may seem significant but are typical when you toss even a perfectly balanced coin so many times.

Shi's job was to devise analytical techniques to determine whether the "finding" of a SNP's greater likelihood among schizophrenics was real or spurious. The genomic region on chromosome 6 survived this rigorous statistical test.

"These findings show that our genetic methods are working, and that the genetic underpinnings of schizophrenia can be understood," said Levinson. "Similar methods have produced critical new discoveries in many other common diseases, once very large numbers of people could be studied. Now we see that the same approach works for psychiatric disorders like schizophrenia."

The three papers (in no particular order):

Nature doi:10.1038/nature08185

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

The International Schizophrenia Consortium

Abstract

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%1, 2. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

Link

Nature doi:10.1038/nature08186

Common variants conferring risk of schizophrenia

Hreinn Stefansson et al.

Abstract

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders1, 2, 3. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized4. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Link

Nature doi:10.1038/nature08192

Common variants on chromosome 6p22.1 are associated with schizophrenia

Jianxin Shi et al.

Abstract

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission1. Recent studies implicate rare, large, high-penetrance copy number variants in some cases2, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 times 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

Link

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.

Major Histocompatibility Complex and Mate Selection in Africans and Europeans

This is a very important study posted in the freely available PLoS Genetics. The Major Histocompatibility Complex (MHC) has been implicated in attractiveness, and has even been made the focus of dna-based dating.

Unlike many other human traits, say nose length, where people tend to mate with others like themselves, the opposite has been suggested for the MHC. The reasoning goes, that MHC is related to disease-resistance, and couples dissimilar in it will produce heterozygous children that will be more capable of fighting disease.

To test this hypothesis, scientists looked at how dissimilar spouses actually are in the MHC, comparing it with their genome-wide dissimilarity: the question is, do they differ in the MHC more or less than they do across the entire genome.

The answer was surprising. African spouses tended to be similar to each other -compared to random African individuals- indicating that there was a tendency for people to marry those genetically close to them. However, no significant pattern emerged for the MHC, i.e., they didn't tend to marry those who were either similar or dissimilar to them.

Europeans spouses, on the other hand, were more dissimilar to each other in the MHC than random individuals, and more dissimilar in the MHC than in the rest of the genome. So, this is strong evidence for assortative mating of MHC-dissimilar Europeans, but not MHC-dissimilar Africans.

Here is the authors' explanation:

On the other hand, Yoruba couples exhibited a significant genome-wide signature of assortative mating, which is likely to result from socio-demographic processes specific to this population. The Yoruba are still organized in paternal lineages, which are exogamous units [32] and C. Adebamowo, personal communication. Although we do not have specific ethnological data collected with the Yoruba samples to explain our observations, a process in which matrimonial exchanges between genealogically related lineages are more frequent than matrimonial exchanges between genealogically unrelated lineages could have left such a genome-wide signature. On the contrary, for the MHC region, no significant pattern of similarity/dissimilarity was observed, at either the molecular level or the serological level. Several hypotheses can be proposed to explain this observation: firstly, it is possible either that the MHC is not involved in mate choice in this population, or that social factors are relatively more important than the MHC and that the sample size here does not allow detection of MHC effect on mate choice.

In other words, the genetic similarity between Yoruban spouses may be the result of population structure, in which individuals mate within social units, rather than with individuals from the entire population.

On the other hand, the unimportance of the MHC for Yoruban mating can be attributed to either its unimportance for Yorubans, or to the fact that "social factors" rather than "good chemistry" play a bigger role in mate choice. A test on other African populations with different social patterns would, perhaps, resolve this puzzle.

PLoS Genetics doi: 0.1371/journal.pgen.1000184

Is Mate Choice in Humans MHC-Dependent?

Raphaëlle Chaix et al.

Abstract

In several species, including rodents and fish, it has been shown that the Major Histocompatibility Complex (MHC) influences mating preferences and, in some cases, that this may be mediated by preferences based on body odour. In humans, the picture has been less clear. Several studies have reported a tendency for humans to prefer MHC-dissimilar mates, a sexual selection that would favour the production of MHC-heterozygous offspring, who would be more resistant to pathogens, but these results are unsupported by other studies. Here, we report analyses of genome-wide genotype data (from the HapMap II dataset) and HLA types in African and European American couples to test whether humans tend to choose MHC-dissimilar mates. In order to distinguish MHC-specific effects from genome-wide effects, the pattern of similarity in the MHC region is compared to the pattern in the rest of the genome. African spouses show no significant pattern of similarity/dissimilarity across the MHC region (relatedness coefficient, R = 0.015, p = 0.23), whereas across the genome, they are more similar than random pairs of individuals (genome-wide R = 0.00185, p<10−3). We discuss several explanations for these observations, including demographic effects. On the other hand, the sampled European American couples are significantly more MHC-dissimilar than random pairs of individuals (R = −0.043, p = 0.015), and this pattern of dissimilarity is extreme when compared to the rest of the genome, both globally (genome-wide R = −0.00016, p = 0.739) and when broken into windows having the same length and recombination rate as the MHC (only nine genomic regions exhibit a higher level of genetic dissimilarity between spouses than does the MHC). This study thus supports the hypothesis that the MHC influences mate choice in some human populations.

Link

Ancient balanced polymorphism preserved in Chinese ethnic minorities

Interesting preprint from AJHG which reports the discovery of a balanced polymorphism at high frequency in some Chinese ethnic minorities, at a smaller frequency in the Han, and its absence in Europeans and a limited sample of Africans. The great age of this polymorphism makes it a likely candidate for being of local East Asian origin before the emergence of anatomically modern humans.

American Journal of Human Genetics (preprint)

An ancient, balanced polymorphism in a regulatory region of human MHC is retained in Chinese minorities but lost worldwide

Xiaoyi Liu et al.

Summary

The coding regions of many MHC (HLA in human) molecules are believed to be subjected to balancing selection. But it is less certain whether the regulatory regions of such coding sequences are also subjected to the same type of selection. Here we studied the polymorphism of the regulatory regions of the HLA-DPA1 and -DPB1 genes among ethnic minorities in southwestern China. Phylogenetic analysis revealed two deep clades over 10 million years old. Linkage disequilibrium between the regulatory and coding regions of DPA1 is almost complete, hinting at coadaptive balancing selection on the entire region. Thus, the molecular mechanism of balancing selection in MHC may involve expression modulation, in addition to coding region polymorphisms. While the frequency of this polymorphism is greater than 30% in some ethnic minorities, it decreases to less than 5% among southern Han Chinese and vanishes among Europeans. As suspected, some ancient balanced polymorphisms, lost in major populations, still exist in isolated ethnicities. These isolated populations could thus contribute disproportionately to the total diversity of modern humans.

Heterozygosity and attractiveness

According to a new study, men who are heterozygous at three loci of the major histocompatibility complex are judged to be more attractive by women. Such men may be more resilient to infection, and hence they might live longer, or infect their spouses and offspring less; therefore, women may have evolved a preference for the phenotypical cues of MHC-heterozygous males, and such males have come to be seen as more attractive.

Evolution and Human Behavior
Volume 26, Issue 3 , May 2005, Pages 213-226

MHC-heterozygosity and human facial attractiveness

S. Craig Roberts et al.

Abstract

Females gain direct or indirect fitness benefits by choosing between males with traits indicating “good genes,” but we usually know very little about the nature of these genes. However, it has been suggested that genetic quality may often be defined as heterozygosity at certain loci. Here, we show that heterozygosity at three key loci in the major histocompatibility complex (MHC) is associated with facial attractiveness: Faces of men who are heterozygous at all three loci are judged more attractive by women than faces of men who are homozygous at one or more of these loci. MHC genes code for proteins involved in immune response. Consistent with this function, faces of MHC heterozygotes are also perceived to be healthier. In a separate test, in the absence of any other cues, patches of skin from the cheeks of heterozygotes are judged healthier than skin of homozygotes, and these ratings correlate with attractiveness judgements for the whole face. Because levels of MHC similarity can influence mate preferences in animals and humans, we conducted a second experiment with genotyped women raters, finding that preferences for heterozygosity are independent of the degree of MHC similarity between the men and the female raters. Our results are the first to directly link facial attractiveness and a measure of genetic quality and suggest a mechanism to help explain common consensus concerning individual attractiveness. In a relatively monogamous species like humans, evolutionary benefits from choosing heterozygous mates could include prolonged parental care and reduced risk of contracting disease for females and their offspring.

Link

The origin of domestic animals

Keats' Telescope posts a link to a study on the origin of domestic animals. The low level of mtDNA diversity in many domestic animals indicates that these are descended from only a few domestication events. However, modern domestic animals seem to also possess some evidence of genes of "wild" origin, indicating that after they were domesticated they did not become isolated genetically, but continued to be crossed with wild animals, either intentionally (by humans), or by accident.

Trends in Genetics
Volume 21, Issue 4 , April 2005, Pages 214-218

Genes of domestic mammals augmented by backcrossing with wild ancestors

Carles Vilà et al.

Both archaeological data and the presence of few mitochondrial DNA lineages suggest that most widespread domestic mammals (cattle, sheep, goats, pigs and dogs) derive from only a handful of domestication events. However, each of these species shows a high level of diversity at the nuclear genes of the major histocompatibility complex (MHC). Through simulations incorporating various degrees of population subdivision, growth rate and selection, we demonstrate that the numerous MHC DRB alleles that are present in modern domestic mammals implies that substantial backcrossing with wild ancestors, either accidental or intentional, has been important in shaping the genetic diversity of our domesticates. These results support the view that, contrary to common assumption, domestic and wild lineages might not have been clearly separated throughout their history.

Link