ESHG 2013 abstracts

A couple of weeks before the ESHG 2013 conference, here are a few abstracts that caught my eye. Feel free to point to more interesting presentations in the comments section.

• J16.05 - Checking the hypothesis of a Balkan origin of the Armenians
• P17.5 - Y chromosome haplogroup analysis to estimate genetic origin of Balts
• J16.27 - Armenian Highland as a transition corridor for the spread of Neolithic agriculturists
• J16.14 - In Search of the Origin of Haplogroup J1-P58
• J16.03 - Y-chromosome haplogroup analysis in the Besermyan ethnic group
• P17.4 - Mitochondrial DNA Analysis of the Southeast European Genetic Variation Reveals a New, Local Subbranching in Hg X2
• P16.085 - Population diversity and history of the Indian subcontinent: Uncovering the deeper mosaic of sub-structuring and the intricate network of dispersals
• J16.43 - Ancient mtDNA diversity in Bulgaria
• P16.072 - Mitochondrial DNA diversity in medieval and modern Romanian population
• P16.012 - Frequency analysis of the CCR5-Delta32 allele in medieval and modern Romanian population
• J16.78 - The gene pool of Argyn in the context of generic structure of Kazakhs according to data on SNP-Y-Chromosome markers.

Romans and AIDS resistance

Via the Herald:

Scientists believe the invading Romans caused the loss of a genetic shield that makes some people resistant to infection by the Aids virus, HIV.

The gene variant, called CCR5-Delta32, impairs the ability of HIV to enter white blood cells.

People with the mutation are not as easily infected by the virus and take longer to develop full-blown Aids.

Generally, only Europeans and western Asians carry the variant, which becomes less widespread as you move south.

More than 15% of people in some parts of northern Europe have CCR5-Delta32, compared with fewer than 4% of Greeks.

...

He does not think the Romans spread a different version of the gene into their colonies by breeding with the natives.

A more likely explanation, he believes, is that they introduced a fatal disease to which carriers of the CCE5-Delta32 variant were unusually susceptible.

New Scientist magazine reported: "As the Romans moved north, this disease killed people with the variant.

It's hard to envision a disease that would be limited to the territory of the Roman Empire. The Roman frontier was fluid, with both Romans trading beyond it, and barbarians moving into Roman territory; it's hard to imagine how a disease could be "contained" within the territory of the Empire. Moreover, I don't really see a good candidate for a really dramatic Empire-wide epidemic, which would surely have been noticed by historians.

Via the BBC:

In countries inside the borders of the empire for longer periods, such as Spain, Italy and Greece, the frequency of the CCR5-delta32 gene, which offers some protection against HIV, is between 0% and 6%.

Countries at the fringe of the empire, such as Germany, and modern England, the rate is between 8% and 11.8%, while in countries never conquered by Rome, the rate is greater than this.

...

However, some researchers believe that infections may have played a role - but in reverse -increasing rather than decreasing the frequency of the variant.

Researchers at the University of Liverpool suggested that the variant may have offered protection against pandemics such as the Black Death which swept Europe on a regular basis during and after the Roman era.

These, said the Liverpool researchers, were illnesses which may have been lethal to people without the gene variant, raising its frequency from one in 20,000 people to approximately 10% in Northern Europe.

Infection, Genetics and Evolution doi:10.1016/j.meegid.2008.08.007

Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?

Eric Faure and Manuela Royer-Carenzi

We studied the possible effects of the expansion of ancient Mediterranean civilizations during the five centuries before and after Christ on the European distribution of the mutant allele for the chemokine receptor gene CCR5 which has a 32-bp deletion (CCR5-Delta32). There is a strong evidence for the unitary origin of the CCR5-Delta32 mutation, this it is found principally in Europe and Western Asia, with generally a north-south downhill cline frequency. Homozygous carriers of this mutation show a resistance to HIV-1 infection and a slower progression towards AIDS. However, HIV has clearly emerged too recently to have been the selective force on CCR5. Our analyses showed strong negative correlations in Europe between the allele frequency and two historical parameters, i.e. the first colonization dates by the great ancient Mediterranean civilizations, and the distances from the Northern frontiers of the Roman Empire in its greatest expansion. Moreover, other studies have shown that the deletion frequencies in both German Bronze Age and Swedish Neolithic populations were similar to those found in the corresponding modern populations, and this deletion has been found in ancient DNA of around 7000 years ago, suggesting that in the past, the deletion frequency could have been relatively high in European populations. In addition, in West Nile virus pathogenesis, CCR5 plays an antimicrobial role showing that host genetic factors are highly pathogen-specific. Our results added to all these previous data suggest that the actual European allele frequency distribution might not be due to genes spreading, but to a negative selection resulting in the spread of pathogens principally during Roman expansion. Indeed, as gene flows from colonizers to European native populations were extremely low, the mutational changes might be associated with vulnerability to imported infections. To date, the nature of the parasites remains unknown; however, zoonoses could be incriminated.

Link

DNA8 Conference

From the program of the 8th International Conference on Ancient DNA and Associated Biomolecules which took place last October.

Greenblatt Charles L., Towards the Molecular Archaeology of the Holyland

The history of the Israelite origin and residence in the area of present day
Israel stretches back through a number of important archaeological periods;
from the Early Bronze Age (3,500 BC), through the Iron Age (1150 – 586 BC),
the Hellenistic (300 BC) and the late Roman period (70 – 400 CE). Several
major questions dominate the archaeology of the Holyland. They concern the
origin of the Israelites, the maintenance of their social structure (that is the
priestly class, the kings, prophets and rabbis), and the conquest of the land
from the Cannanites. More generally stated, how did these nomads with a
record of bad kings, corrupt priests, conquest by major enemies – Egyptians,
Assyrians, Arameans (Syrians), Babylonians, Persians, Greeks, and Romans,
persist and even become dominant in the land? Molecular biology and aDNA
research can lend insights into some of these questions. Central to the
successful settlement was plant and animal domestication. Recently we have
been able to do the evolutionary tree of the indigenous grape and traced its
relationship to those of the Mediterranean basin. Parchments from the Dead
Sea Scrolls provide molecular signatures of early goat domesticates. Y
chromosome analysis shows relatedness of the Jews to Mesopotamian
populations, and on the same chromosome gene clusters define the priestly
class’s origin as occurring before the separation of the mainstreams of the
Jews. We are also gaining a better idea of the diseases of the Biblical period,
with a recent finding of a member of the elite class co-infected with leprosy
and tuberculosis.

Baca M. et al, Was Inca from Ccopan genetically different from his subjects?

Polish archeological team headed by dr M. Ziolkowski discovered in Ccopan
site in Peru a rich grave dated for XV century. Most probably, the grave
belonged to an Inca of high rank. We have amplified and analyzed the 290 bp
mtDNA fragment from the remnants (teeth) found in this grave and from the
remnants of 4 individuals buried nearby in much poorer graves. The aim of
this study is to verify the hypothesis that Inca leaders were ethnically different
from their subjects. We are planning to analyze mtDNA sequences from the
greater number of individual and to extend our study on the chromosome Y
sequences.

Cipollaro M., del Gaudio S., Pompeii and Murecine: tales from ancient DNA

Ancient DNA extracted from individuals found in three houses located in
Pompeii and Murecine has been studied. Mitochondrial DNA and single genes
analysis has been carried out beside histochemical evaluation of bone tissue.
Data are shown concerning: a possible pedigree of Polybius house
inhabitants, the mitochondrial hypervariable segment I sequences of Murecine
remains and a single gene fragment sequence of three equids found in "Casti
Amanti" house.

The following abstract seems to contradict directly the recent paper on recent selection of Europeans' capacity to digest milk.

Fulge M., Renneberg R., Hummel S., Herrmann B., Lactose persistence in prehistoric individuals

Introduction: The dietary habits of ancient populations are often issues of
stake. With the domestication of animals like cattle, sheep and goat these
habits changed. The question since when milk and its products were used as
daily life aliment is of special interest, because the normal condition in
mammals is that after the lactation period they are not able to digest lactose.
In 95% of the European individuals the state of lactose tolerance maintains,
whereas in Africa and Asia 95% are lactose intolerant.
The point of time and the place of development of the lactase persistence are
in request. Two different theories of it exist. One is that the lactose tolerance
developed in Anatolia in the Neolithic period and would have spread in Europe
8000 years ago. The other theory declares a nomadic tribe (Kurgan culture)
as population of origin. Following this theory the lactose tolerance would have
spread 4500-3500 years ago.
One method to detect the status of the digesting ability of lactose is to
determine the pointmutation C/T (-13910) which is linked to the lactase gene.
If a T is realized (homo- or heterozygote) you are able to digest lactose. In this
study we investigated this mutation in 38 individuals of the Bronze Age
Lichtenstein Cave and in nine Celtic individuals from Manching to get a clue
when the lactose tolerance was spread in Europe.
Materials and Methods: The DNA was extracted of femora and mandibles with
a silica-based method on the EZ1-extraction robot (Qiagen). For detecting the
pointmutaion a dye labelled primer was designed. The upper primer contained
a mismatch which permits the digestion with HinfI if thymidin is realized at the
position 13910. For proving the authenticity of the results the lactose Primer
was coamplified with six autosomal STRs.
Results and Perspective: The lactose genotype could be amplified and
authenticated in 27 Individuals of the Lichtenstein Cave. About 60% were
lactose tolerant and around 40% were intolerant. Similar results were detected
in the nine Celtic individuals: around 50% was lactose intolerant. These high
rates of intolerant individuals suggest that even if stock farming was done
consume of milk was not a daily habit. These results give a hint that lactose
tolerance was not only spread 8000 years ago. For proving this thesis earlier
and later populations should be analysed.

Krause S., Scholten A., Hummel S., Cystic Fibrosis and Hemochromatosis in a Bronze Age population

Introduction: In present day Central European populations, Cystic Fibrosis
(CF) and Hereditary Hemochromatosis (HH) are the most common genetically
determined inherited diseases. Both defects are inherited in an autosomal
recessive mode. While for CF the rate of homozygosity is about 1:2000, the
value is even higher in HH (1:400). Possible reasons for the high incidence
are heterozygous advantages. In case of CF, individuals heterozygous for the
ΔF508 mutation do not suffer from dehydration in relation to diarrhoea, which
may have positively influenced the survival rate for newborn and infant
individuals in historic times. In case of HH which arises from SNPs called
C282Y and H63D women are less prone to suffer from the consequences of
iron loss due to menstrual bleeding and enhanced iron requirements during
pregnancy and lactation. Deviating alleles are thought to have accumulated
comparatively recently in European populations. Methods: The well preserved
Bronze Age skeletal remains of the Lichtenstein Cave from the Harz
mountains, which proved to be an invaluable genetic archive already in other
contexts (e.g. Δ32 ccr5, Hummel et al. 2005) now enabled to investigate the
genetic markers responsible for CF and HH. DNA extracts were processed
from bone powder of all 39 individuals with the help of the EZ1 Biorobot
(Qiagen) (cf. Poster of Wenzel et al.). The primers for the detection of the 3
bp-deletion ΔF508 on chromosome 7 indicating CF were co-amplified with the
STR typing kit Profiler Plus (Applied Biosystems). Therefore, each result for
ΔF508 is accompanied by a full genetic fingerprint ensuring the authenticity of
the amplification result. In case of HH the primers for C282Y and H63D were
each co-amplified with an octaplex STR amplification system, again
generating genetic fingerprint data. The determination of the SNPs were then
carried out through RFLP analysis of the entire amplification product. Results:
None of the Lichtenstein cave individuals revealed the 3bp deletion at the
ΔF508 locus. This result indicates that the increased allele frequencies of
ΔF508 in present day populations may indeed be a result of the younger
European history. In contrast, the typing of C282Y and H63D for HH indicates
that at least the polymorphism for C282Y must be older than the 2000 years
assumed since we found 8% of the 3000 years old Lichtenstein cave
individuals being heterozygous. However, none of the individuals is suspect to
have suffered from HH which requires the compound heterozygous state for
both loci. Although we found 36,5% of the individuals being either
homozygous (13,5%) or heterozygous (23%) for the mutation in H63D none of
these individuals is showing the mutation for C282Y as well. Again, the results
prove that the polymorphism H63D is much older than 3000 years.

Ovchinnikov I. et al., The Pleistocene Horse mtDNA Diversity in Sungir, Russia

Renneberg R. et al., Ancient DNA analysis of bones and textiles of prehispanic
populations settled in the Palpa Valley/Peru

Zawicki P. et al., Presence of Δ32CCR5 in medieval specimens from Poland

ESHG 2007

In this summer's European Society of Human Genetics conference one of the presentations will be on "Origin of the Etruscans: novel clues from the Y chromosome lineages". I wonder if my prediction of a high representation of Y haplogroup J1 (almost equivalent to J*(xJ2)) among the ancient Etruscans will be supported by this research. Unfortunately, I did not see an abstract posted yet. Another interesting title is "Epidemics of viral haemorrhagic fever in Medieval times as a possible selection pressure for CCR5del32 in Europe: new insights from Croatian island isolates". This involves an allele which confers resistance to the HIV virus and which is found frequently particularly in Northern Europeans, so perhaps its presence may be the result of some past selection effect against a different disease.

HapMap publication explosion

Haplotype map offers new insights into human disease, evolution

Cambridge, MA, Wed., Oct. 26, 2005 – In several papers published this week in Nature, Nature Genetics, PLoS Biology and Genome Research, Broad researchers and an international set of collaborators announce substantial advances in relating human genetic variation to disease and understanding human evolutionary history.

This flurry of high-profile studies are grounded in data described in a significant paper published in the Oct. 27 issue of the journal Nature by an international consortium of more than 200 researchers from Canada, China, Japan, Nigeria, the United Kingdom and the United States. In this paper, the authors describe the common patterns of genetic variation in human DNA samples collected from four sites around the world. The Consortium's findings provide overwhelming evidence for previous scientific work suggesting that genetic variants located physically close to each other are collectively inherited as groups, called haplotypes. The comprehensive catalog of all of these blocks, known as the "HapMap," which is now publicly available to the biomedical research community, has already accelerated the search for gene variants involved in common diseases and brought new insights into the genes involved in human evolution.

...

In line with the Broad Institute's commitment to building critical resources for the scientific community, HapMap data are freely available in several public databases, including the HapMap Data Coordination Center (www.hapmap.org), the NIH-funded National Center for Biotechnology Information's dbSNP (www.ncbi.nlm.nih.gov/SNP/index.html) and the JSNP Database in Japan (snp.ims.u-tokyo.ac.jp). Further information can also be found at the Broad Institute's web site (www.broad.mit.edu).

Read more:

HapMap Could Yield Genetic Clues to Many Diseases Forbes
HapMap Catalogue of Human Genetic Variation Published Bio-IT World
Phase I of HapMap complete The Scientist

Researchers have released a public database of human genetic variation, designed to help scientists study the effects of small genetic differences on health, reports an international consortium in this week's Nature. The findings suggest that only 260,000 to 470,000 single nucleotide polymorphisms (SNPs) are needed to capture all the common genetic variation in the populations studied, despite the fact that there are an estimated 10 million common SNPs in the human genome.

List of papers/editorials/commentaries (most require access):

Nature Deeper into the genome
Nature Genomics: Understanding human diversity
Nature A haplotype map of the human genome

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

Nature Genetics Efficiency and power in genetic association studies

We investigated selection and analysis of tag SNPs for genome-wide association studies by specifically examining the relationship between investment in genotyping and statistical power. Do pairwise or multimarker methods maximize efficiency and power? To what extent is power compromised when tags are selected from an incomplete resource such as HapMap? We addressed these questions using genotype data from the HapMap ENCODE project, association studies simulated under a realistic disease model, and empirical correction for multiple hypothesis testing. We demonstrate a haplotype-based tagging method that uniformly outperforms single-marker tests and methods for prioritization that markedly increase tagging efficiency. Examining all observed haplotypes for association, rather than just those that are proxies for known SNPs, increases power to detect rare causal alleles, at the cost of reduced power to detect common causal alleles. Power is robust to the completeness of the reference panel from which tags are selected. These findings have implications for prioritizing tag SNPs and interpreting association studies.

Genome Research
Calibrating a coalescent simulation of human genome sequence variation

Population genetic models play an important role in human genetic research, connecting empirical observations about sequence variation with hypotheses about underlying historical and biological causes. More specifically, models are used to compare empirical measures of sequence variation, linkage disequilibrium (LD), and selection to expectations under a "null" distribution. In the absence of detailed information about human demographic history, and about variation in mutation and recombination rates, simulations have of necessity used arbitrary models, usually simple ones. With the advent of large empirical data sets, it is now possible to calibrate population genetic models with genome-wide data, permitting for the first time the generation of data that are consistent with empirical data across a wide range of characteristics. We present here the first such calibrated model and show that, while still arbitrary, it successfully generates simulated data (for three populations) that closely resemble empirical data in allele frequency, linkage disequilibrium, and population differentiation. No assertion is made about the accuracy of the proposed historical and recombination model, but its ability to generate realistic data meets a long-standing need among geneticists. We anticipate that this model, for which software is publicly available, and others like it will have numerous applications in empirical studies of human genetics.

PLoS Biology The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele

The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles.

The origin of an HIV-Resistance Allele

Via John Hawks. This study is a good example of how non-uniform selection can change allele frequencies in a way that an allele may reach its highest frequency in a region different from the one where it originated. See also HIV Resistance mutation in the Bronze Age.

PLoS Biology Volume 3, Issue 11

The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele

John Novembre et al.

The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles.

Link