human leukocyte antigen (hla) haplotypes and human biodiversity

*update 10/27: for more on human leukocyte antigens (hla’s), see chris davies’ blog right here! (^_^)
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over the past few months, commenter chris davies has left several interesting comments here on the blog about hla haplotypes (see here and here and here and here for example) — something about which, like so very many things, i know absolutely NOTHING.

i asked chris if he’d help alleviate my ignorance by writing a post on the topic, and he has graciously obliged (thanks, chris!). so, without further ado, here’s chris’ introduction to hla!:

An Introduction to HLA (Human Leukocyte Antigens)

I would like to thank HBD Chick, who recently asked me if I wanted to write a guest post here about Human Leukocyte Antigens (HLA). I have been a reader of this blog for several months now, and I really enjoy it. This blog is among the most innovative of the HBD-related blogs out there and takes a completely different approach to the subject. So it is a pleasure to write a post here, as I don’t write a blog myself.

In the comments section on some posts here recently I have talked about ‘HLA haplotypes’. I have had an interest in HLA haplotypes for a few years, following discussions with a molecular biologist who writes (or rather wrote) in newsgroups including Usenet. But what are ‘HLA haplotypes’, and more importantly what is their usefulness or relevance to those of us with an interest in ‘HBD’?

‘HLA’ means Human Leukocyte Antigen. The HLA system is simply the name given to the human version of the Major Histocompatibility Complex (MHC). MHC genes are found in most vertebrates, and this group of genes can be found on chromosome 6.

HLA genes are important in immune function and disease defence. There are three classes: Class I (A,B,C); Class II (DP, DM, DOA, DOB, DQ, DR); and Class III. All play different roles.

In addition to conferring resistance or susceptibility to various diseases and conditions (eg autoimmune diseases, such as type I diabetes), they are also vitally important in organ and bone marrow transplants. For example, if a donor is not a close enough match in terms of HLA, an organ could be rejected. Because diversity of HLAs in human populations is a part of disease resistance, it is very uncommon to find two unrelated individuals with identical HLA molecules at all loci.

In addition, it has been claimed that HLA may play a role in human mate selection through people’s perception of the odor of other people.

HLA haplotypes are like strings of HLA genes by chromosome, with one being inherited maternally and the other paternally. A multigene haplotype is a set of inherited alleles covering several genes, or gene-alleles. Common multigene haplotypes are generally the result of identity by descent from a common ancestor. As distance from the ancestor increases, chromosomal recombination causes multigene haplotypes to fragment.

An example of an HLA haplotype is shown below:

A*01:01 ; C*07:01 ; B*08:01 ; DRB1*03:01 ; DQA1*05:01 ; DQB1*02:01
[Which by serotyping, is more simply: A1-Cw7-B8-DR3-DQ2].

This particular haplotype btw is found at high frequency among people of North-West European descent, including Irish, British, Dutch, Germans, Scandinavians, and of course a high percentage of Americans and Australians. It is associated with autoimmune disorders like coeliac disease, and allergic diseases like hayfever and asthma.

In addition to medical use, HLA haplotypes can also be used as a means of tracing migrations in the human population as they are like a fingerprint of an event that has occurred in evolution.

So alongside Y Chromosome DNA and Mitochondrial DNA (mtDNA) markers, HLA haplotypes are useful tools for molecular anthropologists in determining evolutionary links between ancient and modern human populations. They also help to determine closeness of relationships between or within populations, and commonality of geographical origin between groups. Therefore patterns of migration and settlement can be traced, giving insight into how contemporary populations have formed and progressed over time.

Because the HLA system is under selection, diversity in HLA should be looked at in conjunction with other markers like Y-DNA and mtDNA in building a bigger picture when tracing migrations of modern humans.

However, HLA has several advantages over Y-DNA and mtDNA. mtDNA is often biased towards the founders in a core population and can show a punctuated distribution, while Y-DNA is biased more towards relatively recent migrations, and with both of these markers the effects of genetic drift are more rapid. With HLA there is intense heterozygous selection which works to preserve diversity.

Also with HLA, one tends not to see a punctuated distribution of haplotypes across geographical regions between groups, but rather one sees a fluidity of migrations tracing back to their original source population. Examples of this occur when one looks at diversity of HLA in northern Africa, which appears to be the source for a number of haplotypes that migrated into Europe in the Holocene. This picture is less clear from looking at mtDNA or Y-DNA data only.

Finally, the other advantage of HLA is the sheer volume of data available. [See: www.allelefrequencies.net]. The numbers of people worldwide who have been typed for HLA are huge. There are nearly 22 million donors and blood cord units in the BMDW (Bone Marrow Donors Worldwide) database, encompassing many different ethnicities and nationalities with hundreds of thousands of HLA alleles and extended haplotypes identified. Y-DNA and mtDNA cannot offer this volume of data. Whether used for tracing ancient human migrations, or researching diseases in different populations, this data can be extremely helpful.

The association of HLA haplotypes in populations with certain diseases in Western countries is interesting to consider from an HBD perspective. For example, if resistance or susceptibility to obesity, heart disease, diabetes, breast cancer, etc. are all affected by HLA type, then there could be wildly varying outcomes between different population groups, in addition to the effects of environmental or lifestyle factors.

This in turn could have serious implications. For example, certain disease-related charities’ fund-raising campaigns are aimed at convincing the general public to donate cash on the basis that everyone is almost equally at risk from that particular disease, when different ethnic groups living in the same country with the same lifestyle may often vary in risk considerably from very high risk down to very low risk, with HLA type being an important determining factor. But the charity may not publicise this information in order not to jeopardise their fund-raising. This, I should stress, is speculation on my part however.

If want to find out more about Human Leukocyte Antigens, please refer to some of the sources listed below:

References
– The Allele Frequency Net Database (AFND). A database and online repository for immune gene frequencies in worldwide populations: [www.allelefrequencies.net]
“Tracking Human Migrations by the Analysis of the Distribution of HLA Alleles, Lineages and Haplotypes in Closed and Open Populations.” [Fernandez Vina, M. et al, 2012].
“HLA 1991: Proceedings of the Eleventh International Histocompatibility Workshop and Conference” (Volumes I & II) [Kimoshi Tsuji; Miki Aizawa; Takehiko Sasazuki] Oxford Science Publications, 1991.
– “HLA-Net: A European Network of the HLA Diversity for Histocompatibility, Clinical Transplantation, Epidemiological and Population Genetics.” [www.hla-net.eu].
– “AHPD: Analysis of HLA Population Data to Reconstruct the History of Modern Humans and Infer the Role of Natural Selection.” [geneva.unige.ch/ahpd].
“Challenging Views on the Peopling of East Asia: the Story According to HLA Markers.” [Di D, Sanchez-Mazas A.]. Am J Phys Anthropol. 2011 May; 145(1):81-96.doi:10.1002/ajpa.21470.Epub2011Jan4. PMID:21484761 [Pubmed – indexed for MEDLINE].
– Wikipedia: “Human Leukocyte Antigen.”
– Wikipedia: “Major Histocompatibility Complex.”

(note: comments do not require an email. gene map of the human leukocyte antigen (hla) region!)

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13 Comments

  1. There is one thing that may be relevant to the topic that reoccurs here. I found this:

    “In 1995 Claus Wedekind found that in a group of female college students who smelled T-shirts worn by male students for two nights (without deodorant, cologne, or scented soaps), by far most women chose shirts worn by men of dissimilar MHCs, a preference reversed if the women were on oral contraceptives.[16] Results of a 2002 experiment likewise suggest HLA-associated odors influence odor preference and may mediate social cues.[17] In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs alike their own,[18] although without oral contraceptives, the women showed no particular preference.[19] There are no studies on the extent to which odor preference determines mate selection (or vice versa).”

    http://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_in_sexual_mate_selection

    The above study was presumable done on WEIRD women. Has a similar study been done on a population with more inbreeding?

    Reply

  2. Szopeno: “Thanks a lot gor this guest post, chris! It was very interesting.”

    Thank you Szopeno..

    Reply

  3. Andrew, yes this was what I briefly mentioned. I believe it has been suggested that the knock-on effect of this could be that if women are taking oral contaceptives when they first enter a relationship then their choice of mate has been distorted by the effect of the contraception. So that as soon as they stop taking the contraception they could lose sexual attraction to their mate. This is an interesting complement to the link which HBD Chick posted yesterday about the effects of the Pill altering women’s voting patterns, thanks for posting Andrew.

    What caught my attention from that Wikipedia page which Andrew gave the link to is this part [under ‘MHC & Sexual Conflict’]:-

    “If males attempt to thwart female mate choice by mating with a female against her will, sexual conflict may interfere with the choice for compatibility at the MHC genes.
    In Chinook salmon Oncorhyncus tshawytscha, females were shown to act more aggressively towards MHC-similar males than MHC-dissimilar males, suggesting the presence of female mate choice. Furthermore, males also directed aggression at MHC-similar females. This was accompanied by male harassment of unreceptive females; however, there was a positive correlation between male aggression and reproductive success. The ability of the males to over-power the females’ original mate choice resulted in the offspring of the targets of male aggression having low genetic diversity. Offspring with high genetic diversity seemed to happen only when the operational sex ratio was female-biased, when females were more likely to be able to exert mate choice, and males were less likely to harass females. These results suggest that sexual conflict may interfere with female mate choice for ‘good’ MHC genes.”

    So if I understand this correctly, among the Chinook salmon that are MHC-similar the female aggressively prevents the male from mating with her, presumably preferring to mate with an MHC-dissimilar male; but if the MHC-similar male is aggressive enough to overpower the aggressive female then there is a stronger likelihood of reproductive success. I wonder if this could be true for humans? Linton who is a regular visitor here suggests that there is a correlation between some degree of consanguinity and higher fertility. In addition there are suggestions that there may be a higher conception rate from rape [see: http://www.politico.com/news/stories/0812/79895.html ], which, if correct, I wonder if ties in with the the positive correlation between male aggression and reproductive success as seen in the Chinook salmon?

    Reply

  4. wouldn’t most of the t-shirts have belonged to men with dissimilar HLAs? it seems like, picking at random women would be unlikely to choose a guy with similar HLA, so how can we really infer anything from that?

    also the abstractabout the salmon doesn’t make it clear if the females were behaving aggressively in a sexual way or in a hostile way.

    Reply

  5. Bleach: “also the abstract about the salmon doesn’t make it clear if the females were behaving aggressively in a sexual way or in a hostile way.”

    I took it that the females were behaving aggressively in a hostile way, ie to prevent the MHC-similar males from mating with them.

    “The ability of the males to over-power the females’ original mate choice resulted in the offspring of the targets of male aggression having low genetic diversity. Offspring with high genetic diversity seemed to happen only when the operational sex ratio was female-biased, when females were more likely to be able to exert mate choice, and males were less likely to harass females.”

    When the sex ratio was female-biased, the females could be more choosy about who they mated with, be less likely to be harrassed, have less need to be aggressive, and more able to exert their preference to mate with MHC-dis-similar males.

    But when the sex ratio was skewed the other way [male-biased], the reverse would occur, so the females needed to be more aggressive to MHC-similar males in those situations in the hope that it might prevent them from successfully mating with them.

    Reply

  6. Andrew: “Has a similar study been done on a population with more inbreeding?”

    Well on the link you provided there are two example of mate-choice in inbred populations, Hutterites and South Amerindian tribes [although these were not ‘odor-preference’ tests]:

    ” One study conducted by Ober et al. examined HLA types from 400 couples in the Hutterite community and found dramatically fewer HLA matches between husbands and wives than expected when considering the social structure of their community. On the other hand, there was no evidence of MHC-based mate choice in the same study of 200 couples from South Amerindian tribes.”

    “Decreased fecundability in Hutterite couples sharing HLA-DR”:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682532/

    “Genetic analysis of HLA in the U.S. Schmiedenleut Hutterites”:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683340/

    “Studies of HLA, Fertility and Mate Choice in a Human Isolate”:
    http://humupd.oxfordjournals.org/content/5/2/103.full.pdf

    Reply

  7. I think it’s important to consider that close-relatedness between people within a population group increases the likelihood that one person will be MHC-similar to another person within that group, but it doesn’t make it inevitable [unless they are siblings]. For example, consider that the top 8 most frequent HLA haplotypes in the highly-inbred Hutterites accounted for 50% of all their haplotypes. Whereas in a sample of more than 13,000 outbred Germans the top 8 most frequent HLA haplotypes accounted for just 19% of total haplotypes – see: http://www.allelefrequencies.net/hla6003a.asp?hla_locus1=&hla_locus2=&hla_locus3=&hla_locus4=&hla_locus5=&hla_locus6=&hla_locus7=&hla_locus8=&hla_population=2812&hla_country=&hla_dataset=&hla_region=&hla_ethnic=&hla_study=&hla_order=order_3&hla_sample_size_pattern=equal&hla_sample_size=&hla_sample_year_pattern=equal&hla_sample_year=&hla_loci=

    Reply

  8. @chris – “So if I understand this correctly, among the Chinook salmon that are MHC-similar the female aggressively prevents the male from mating with her, presumably preferring to mate with an MHC-dissimilar male….”

    if this is at all the same in humans, then … what might this mean wrt, say, mass immigration? will/do women really go for all the foreigners, they presumably being mhc-dissimlar to the native women? =/ studies seem to show that generally most people like to mate with/marry someone like themselves (although maybe with an mhc-dissimilar mate), so perhaps that would put a check on all the women dashing for immigrant men. (i dunno — i’m just thinking out loud here — rambling, really.)

    and, thanks again, chris! really interesting stuff! (^_^)

    Reply

  9. @ and, thanks again, chris! really interesting stuff! (^_^)

    ‘here, here!’

    could it be categorized as HLA as well as guest post? (ok I’ll get mi’ coat)

    Reply

  10. @kate – “could it be categorized as HLA as well as guest post?”

    i made “hla haplotypes” one of the tages. and “human leukocyte antigen” (boy, that’s a mouthful!). (^_^)

    Reply

  11. i made “hla haplotypes” one of the tages.

    you’re right of course but don’t tags draw people in from search engines whilst categories are useful for people who have been drawn in but want to look something up?

    Reply

  12. HBD Chick: “..studies seem to show that generally most people like to mate with/marry someone like themselves (although maybe with an mhc-dissimilar mate)..”

    I found something interesting on PLOS Genetics pertaining to this (see below):

    http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000184

    “Is Mate Choice in Humans MHC-Dependent?”
    Raphaëlle Chaix mail, Chen Cao, Peter Donnelly

    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."

    Reply

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