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Razib found this really fascinating paper which compares differences in gene expression between populations. The results of the study has been published in an open access paper in the American Journal of Human Genetics. The paper is titled, “Evaluation of Genetic Variation Contributing to Differences in Gene Expression between Populations,” and comes from researchers in the University of Chicago and the gene expression company, Affymetrix.

The authors sampled blood from 180 individuals (actually samples were collected from closely related three individuals from 60 different families) and created cell lines from lymphoblastoid cells. The families were either white people from Utah or Yorubans from Nigeria. The cells were lysed and the transcripts were hybridized to microarray chips, which show the expression pattern for lots of genes at once.

How do microarrays work? Well, each chip has microscopic spots loaded with single stranded fragments of one gene. There’s so many spots on each chip that almost all the known genes from the organism of the interest are there. Transcripts, genes that are transcribed and expressed, are single stranded and when they are isolated from cells and washed over microarrays with the little fragments they hybridize or latch onto their complement. The fragments act like anchors since they are bound to the chip. Every time a hybridization event occurs, a florescence reaction also occurs and is picked up by a computerized eye. The amount of transcripts that hybridize can tell us the relative expression level of the gene. The image to your right is an actual scan of a microarray that I’ve put up just so you can see what it looks like. Microarrays aren’t always the best way to compare gene expression differences between populations because SNPs and other allelic differences between genes could affect the hybridization and ultimately the quantification — but there’s really no other high throughput method out there that’s better than this.

Since they were dealing with somewhat differentiated immune system stem cells, the authors limited their results of differences in gene expression they observed. So, it’s not too surprising that they saw big differences between the populations among genes involved in producing antibodies to potential microbial invaders. The unexpected differences were,

“significant differences in expression levels among genes involved in fundamental cellular processes such as ribosomal biogenesis, transfer RNA processing, and Notch-signaling–part of a complex system of communication that governs basic cellular activities and coordinates cell actions.”

Last year we saw the first population comparison of gene expression in the American Journal of Human Genetics paper, “Gene-Expression Variation Within and Among Human Populations,” which found a 17% difference in gene expression between European and African populations. I appreciate this sort of research because our phenotypic differences are not just due to the little differences we harbor in the actual sequence of our DNA but also into the patterns in which genes are expressed or regulated. I’ve said this time and time again, and am happy to see people are continuing to investigate the differences in gene expression between human populations.

STOREY, J. (2007). Gene-Expression Variation Within and Among Human Populations. The American Journal of Human Genetics, 80(3), 502-509. DOI: 10.1086/512017

So there’s this hypotheses that Neandertal extinction was due to cannibalism. This is an alternative but complementary hypothesis to the climate change one. In an upcoming paper in Medical Hypotheses, Simon Underdown investigates this hypotheses by looking at Transmissible Spongiform Encephalopathies (TSEs). The paper is titled, “A potential role for Transmissible Spongiform Encephalopathies in Neanderthal extinction.”

TSEs are also known as prion diseases, a communicable disease where the infectious agent is a malformed protein that replicates by imprinting and transforming other proteins. Most TSEs manifest in the host’s neurological tissues because he or she ate infected nervous tissue. Ultimately, the host’s tissues degenerate and lead to serious problems, most often death. In anthropology, one form of TSEs has been well documented, the spread and eradication of kuru in the Fore from Papua New Guinea.

Before I read the abstract, I assumed Simon looked at Neandertal fossils for paleopathological evidence of spongiform encephalopathies…. at least to some degree. However, the abstract doesn’t definitively indicate whether or not Simon looked into the Neandertal fossil record. Instead, the abstract tells us,

“A modern human hunter-gatherer proxy has been developed and applied as a hypothetical model to the Neanderthals. This hypothesis suggests that the impact of TSEs on the Neanderthals could have been dramatic and have played a large part in contributing to the processes of Neanderthal extinction.”

For those that are curious if there’s evidence of Neandertal cannibalism, you’re in luck. Neandertal cannibalism has been previously documented from remains from sites like Moula-Guercy caves in Ardèche, France, and El Sidrón, Asturias, Spain, so it is totally probable that some got prion diseases. But they were eating each other for 100,000 or so years before the faded out of the picture. You’d think that if they died of prion dieases it wouldn’t take so damn long. Anyways, I just really wonder how Simon went about figuring out if Neandertals really got TSEs.

UNDERDOWN, S. (2008). A potential role for Transmissible Spongiform Encephalopathies in Neanderthal extinction. Medical Hypotheses DOI: 10.1016/j.mehy.2007.12.014

I remember reading the announcement of Sahelanthropus tchadensis (a.k.a. Toumaï) in 2002. It was an exciting time. A cranium is hard to find and is a quite noteworthy for any early hominid. So, it wasn’t surprising that Nature published the findings, “A new hominid from the Upper Miocene of Chad, Central Africa.” But they did so without a firm antiquity for the fossil! See, the primary publication set an estimation of 6 to 7 million years old based upon associated fauna found in the same horizon. No other dating technique was published.

With the possibility of 7 million old date, this fossil threw a big spoke in our understanding of early hominid evolution. Critics weren’t shy to voice their protest. They said the cranium was too squashed to confirm it was a hominid. A virtual reconstruction of the cranium did little to convince anyone. Paleonathropology was still reserved and not willing to fully accept Toumaï as a hominid. If Toumaï was really a hominid, then that would mean when we considered the human-chimpanzee divergence occured to be wrong. All our molecular clocks would be wrong too.

Well, according to this AP release, our anticipation for a real tangible date for the Toumaï should be resolved in next week’s issue of PNAS,

“French fossil hunters have pinned down the age of Toumai, which they contend is the remains of the earliest human ever found, at between 6.8 and 7.2 million years old…

‘The radiochronological data concerning Sahelanthropus tchadensis … is an important cornerstone both for establishing the earliest stages of hominid evolution and for new calibrations of the molecular clock,’ Brunet wrote in a study which will appear in the March 4 edition of the Proceedings of the National Academy of Sciences.

‘Thus, Sahelanthropus tchadensis testifies that the last divergence between chimps and humans is certainly not much more recent than 8 Ma (million years ago.)’”

Wow, I can’t wait. You can be sure to expect me hitting the refresh page and hammering PNAS servers to download a copy of the paper when it comes out. In the mean time, all we have to pine over is the press release, “Oldest hominid discovered is 7 million years old: study.”

The question answering (QA) research group at Carnegie Mellon University has recently released an open source version of their Ephyra Question and Answer System. The software utilizes the internet to answer linguistic questions as well as recognize syntax, word ordering, and tone, using a series of algorithms to produce the most context-appropriate and statistically correct responses. The group hopes to get feedback and evaluations from researchers, so the code is currently being made available to the public.

Ephyra retrieves answers to natural language questions from the Web and other sources. The open source version – OpenEphyra – is almost identical to the system that has been evaluated in the TREC question answering track (http://trec.nist.gov/), except that we had to exclude some 3rd party tools and code with specific hardware requirements. The result is a system that is platform-independent, easy to use, and that can be run on a standard desktop computer and evaluated on questions from the TREC 8-15 evaluations.

While possible applications of the software may span the entirety of Social and Behavioral Sciences, it appears particularly useful to Anthropology and Linguistics as a reconstruction experiment: building the necessary systems of cognition from the inside out. Understanding the subsystems of language in the context of efficiency and necessity may be a useful instrument to developing an understanding of our own language acquisition mechanisms. Furthermore, it may help us further discern differences between animal communication and modern human language.

I know Razib and I are both interested in how skin color is determined. Many different genetic loci have been identified as factors in the skin pigmentation biochemical pathway. It can be a mysterious task, but often all it takes is homology in sequences to clue investigators into considering a new loci as a possible skin color gene. But sequence homology doesn’t tell us the exact function. To really confirm the function of a gene in a pathway, a knock-down or knock-out mutational analysis maybe necessary to correlate a genotype to a phenotype.

In a new announcement issued by the American Society for Biochemistry and Molecular Biology, the protein (NCKX5) of a gene previously identified as an ion exchanger (SLC24A5); one that exchanges sodium for calcium across a membrane, regulated by potassium has been shown to have a role in regulating melanosome production. Here’s a synopsis of the press release,

“…[the researchers] found that NCKX5 is not present on the cell surface, but internally in a compartment known as the trans-Golgi network. This compartment is where new proteins and vesicles are processed, modified and sorted.

When the researchers knocked out NCKX5 in melanocytes (the skin cells that manufacture the melanin pigment), melanin production decreased dramatically. They also demonstrated that changing the ancestral amino acid (alanine) at position 111 to the European form associated with lighter skintone (threonine) reduced NCKX5′s exchanger activity.

While they plan on teasing out the exact biological mechanism, Ginger and colleagues propose that NCKX5 could play a direct role in the trafficking decisions that influence the assembly of melanosomes, the specialized cell vesicles where melanin is produced. Alterations that increase or decrease NCKX5 effectiveness would be expected to influence total skin pigment production.”

I’ve done a quick literature search to see where NCKX5 has been published about before. A recent open access PLoS One paper, “A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation,” identified SLC24A5/NCKX5 as one of the strongest signatures of European-specific selective sweeps. So what does this all mean? Well, the European allele, mentioned in the excerpt above, reduces NCKX5′s ability to function and yields a similar phenotype as if it was completely knocked out (low melanin production). This allele has been fixed really fast within European populations.

These sets of studies are one of the first, in my knowledge, to actually correlate a function of a gene, a phenotype, and the frequency the allele is found within a population.

Kimura, R., Fujimoto, A., Tokunaga, K., Ohashi, J., Harpending, H. (2007). A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation. PLoS ONE, 2(3), e286. DOI: 10.1371/journal.pone.0000286

Couple weeks ago we saw how stable isotope analysis was used in a paleoanthropological context, with a Neandertal tooth. A new study published in this week’s issue of PNAS, extends stable isotope analysis from bones to hair — and this time instead of looking at strontium, a metal, hydrogen and oxygen isotopes were screened. Here’s the title and link to the paper, “Hydrogen and oxygen isotope ratios in human hair are related to geography.”

This study has some important applications to those that work forensic cases. Unfortunately, people don’t always die with their ID cards on them. Investigators often resort to extracting data from the remains in creative ways to solve where the deceased came from, ultimately in order to pin down who the deceased was. DNA analysis can be one of the most definitive ways of identification, only if the probable next of kin also agrees to compare their DNA to the deceased. Other forms rely on morphological comparison, such as the dead person’s teeth to dental records. I’ve discussed how stable isotope analysis can also be applied, to give us a general understand on where in the world this person may have come from.

In this new study hair was screened. Hair’s principle component is a protein called keratin. The amino acids that make up the keratin are synthesized from many different building blocks. Two of these building blocks are hydrogen and oxygen molecules that originally come from dietary and environmental sources. Different versions, or isotopes of hydrogen and oxygen exist in our water and food sources. And their relative amounts get incorporated into our bodies, such as our hair, during biosynthesis. In order to see if different people’s hair relate to regional variation of hydrogen and oxygen isotope levels, the authors of this study, collected discarded hair samples from 65 different barbershops in the United States. They limited their barbershops to those from small towns, just to limit the probability that outsiders would be getting their hair cut.

They also took water samples from the areas they collected the hair, and first correlated if isotope composition of the hair matched up with isotope composition in the regional water samples. They were able to confirm this… there is a linear relationship of hydrogen and oxygen isotopes in hair to hydrogran and oxygen isotopes in water. I’ve included a graph of the relationships between hydrogen isotope ratios and oxygen isotope ratios of human scalp hair and tap water for samples randomly acquired in cities representing 18 states across the United States for your visual entertainment:

Since there exist a relationship of naturally occurring environmental isotopes to those represented in hair, the authors were able to construct a geographical distribution of different isotope levels. They used a tool many archaeologist out there may know of, ArcGIS, to construct their distribution map. This is a really informative map, not only does it show where in the US, the levels of two different hydrogen and oxygen levels, but one could use this map for their own research.

Say, hypothetically, I, a forensic anthropologist, have hair samples from a murder victim and I would like to know where in the United States they may have come from. Sampling the levels of deuterium in the hair, an isotope of hydrogen that has a neutron, I quantify a minus -89 level of deuterium. That amount of deuterium is pretty widespread throughout all of the Midwest. So sampling the oxygen-18 isotope, also represented in the hair sample, would give me another data point to narrow down the results. If my sample comes back at a -13.1 level of oxygen-18, I can have pretty good confidence the hair came from a person who spent some time in the south-eastern Illinois. If I can also correlate the hair, say in color, to missing persons from south-eastern Illinois, I maybe able to identify the person.

I think I went a bit overboard with this explanation of the research but I consider this sorta work really creative. I also really commend the authors because they went above and beyond what most would do. Sampling 65 different barbershops throughout the US is no easy task! I also really commend that they released their map, because I’m sure some missing persons investigator, and the family of missing persons, will be really be grateful to have access to this distribution.

Ehleringer, J.R., Bowen, G.J., Chesson, L.A., West, A.G., Podlesak, D.W., Cerling, T.E. (2008). From the Cover: Hydrogen and oxygen isotope ratios in human hair are related to geography. Proceedings of the National Academy of Sciences, 105(8), 2788-2793. DOI: 10.1073/pnas.0712228105

As will be apparent from the headline, the latest edition of the anthropology blog carnival Four Stone Hearth has hit the cyber-stands, courtesy of Archaeoporn, so be sure to head on over, as there is a very good variety of submissions, s0me of which are from blogs that may not be immediately familiar to regular readers of 4SH.

The next edition will be on March 12th, over at Afarensis.

In last week’s issue of Nature, we saw two really important papers on large scale human population genetic structure be published. The first was, “Proportionally more deleterious genetic variation in European than in African populations,” and the second was, “Genotype, haplotype and copy-number variation in worldwide human populations.” Not to be outdone by Nature, Science also published a very important paper on large scale human population genetic structure, “Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation.” If I wasn’t so deathly ill, I woulda been one of the first to cover it. Thankfully, Razib, Dienekes, Yann, and John Hawks all picked up at least one of these papers and posted about them in their respective blogs.

Now that I’m finally feeling a bit better, I feel really motivated to blog about these papers. I’ll be focusing on the copy number variation Nature paper as well as the variation and relationship of worldwide human populations Science paper, since they come to similar results but from different approaches. I’ll briefly touch on the deleterious genetic variation Nature paper, because it integrates a key concept into the fold.

Before I get into the thick of it, I wanna give a quick run down on a basic population genetic concept, linkage disequilibrium, because it is screened in all of these papers. It is crucial to understand this concept because it is what is fundamentally what is studied in nearly all population genetic studies. Okay, I’m sure you understand the importance… For any given gene, a sequence of DNA that is transcribed there could exist more than one variant or alleles. These alleles can differ from one another in many different ways, but for simplicity’s sake, we’ll consider only single nucleotide polymorphisms (SNPs) today. SNPs are differences in the same sequence of DNA between two or more alleles in only one base pair.

If SNPs exist in coding regions of a gene, they can be synonymous or nonsynonymous mutations. Mutations may have a bad connotation to you, and I’ll explain how synomymous mutations aren’t necessarily bad. The genetic code has a lot of redundancy; every three nucleotides that are in frame, may encode for an amino acid… but since there’s only 20 different amino acids but 64 different combinations of three nucleotides, some combinations encode for the same amino acid. Thus, if a SNP mutation exists in a coding region, but the two variants do not encode for different amino acids, the mutation is called a synonymous mutation. A nonsynonymous mutation can be more impactful, because in this situation, one of the SNPs alter the three base pair codon, and encode for a different amino acid that can change the structure and function of the resultant protein. Does this mean all nonsynonymous mutations are deleterious? No, often the amino acid difference isn’t that big and the protein’s function isn’t changed much… some other times the mutation can be dramatic and create a totally different protein, knocking down or out a cascade of functions the cell, tissue, organ, etc. maybe reliant upon.

SNPs can be inherited, if you didn’t know. Often they are inherited in long blocks, and that’s because of a unique phenomenon called homologous recombination. Homologous recombination occurs during DNA replication, when overlapping segments of DNA have two homologous regions which swap out with one another. I won’t get into the gory details, but it is really cool! If this occurs during meiosis, during gamete formation, the organism that develops from the recombined gametes inherits blocks of SNPs. The length of DNA that travels with a SNP during recombination varies dependent on how ‘new’ the SNP is. Newer SNPs fall in long areas of recombinant DNA, whereas older SNPs travel in shorter areas. People study the length of DNA associated with a SNP to determine ages of new alleles. The difference between lengths of DNA that travel with SNPs is ultimately what is linkage disequilibrium. I won’t get too into haplogroups, other than the situation when one or more SNPs travel together.

Okay that being said, I hope you have a general understanding of what’s happening at a molecular level to makes us vary in segments of DNA. These variations can be used to study our similarities and differences, figure out who came from whom, etc. The first of the papers that I wanna focus in on is Nature‘s “Genotype, haplotype and copy-number variation in worldwide human populations.” The authors of that study took about 526,000 SNPs and 400 copy number variations (the differences in the number of copies of a gene in the genomes of different people) found in 485 people from about 30 different populations. They observe that larger linkage disequilibrium is found in populations that are farther away from Africa? The indicates these “far from Africa” populations are newer compared to African populations, which suggest that African populations are ancestral to outside populations.

Next up to bat is the Science paper on the same topic. This paper one-ups the other in that it has more SNPs (650,000) from 938 people from 51 different populations. It is, as the authors quote, “the most comprehensive characterization to date of human genetic variation.” With more data, the authors were able to reconstruct a phylogenetic tree based upon genetic relationships. I consider the figure they were able to draw up a poster-board example for the Out of Africa hypothesis on human origins, even though I acknowledge John Hawks’ critique that this figure “assumes an Out of Africa” model of human migration, and tells us nothing on the mode and time when this migration occurs. What John Hawks points out is a problem with cladistics. In this study the authors establish an outgroup, the most ancestral group, which happens to be Africa. Thus, they force the phylogenetic tree to pattern as if Out of Africa happened. I don’t think their aim is to show us the timing of the out of Africa event, though, it is merely supposed to document a shared ancestry in Africa.

And here’s where I transition to the last paper, the Nature one on deleterious mutations are more prominent in a newer population, Europeans compared to Africans. This paper, “Proportionally more deleterious genetic variation in European than in African populations” kinda gives us a relative date that Hawks criticizes for. Once, newer populations, ones that are founded by comparatively smaller groups, occupy a niche and expand in populations size — mutations manifest bountifully. Mutations again, can be deleterious as well as advantageous, and in Europeans, a population that’s newer, negative selection has had less time compared to African populations to remove deleterious alleles from European populations.

I’m really happy these three papers came out when they did. Fresh on my mind, is still that one discussion on human genetic identity and human genetic variation. Ancestry and identity are two terms that often get muddled into easily digestible public relations burrito many anthropologists have been fed. There’s a real genetic basis for groups, we haven’t really known about it until now. Part of that has been because we’ve focused on identifying genetic ancestry in one or two loci, such as mtDNA and Y-chromosome, before. Now with more and more SNPs identified, we can point out unique ancestry markers with much greater resolution and begin to understand how our ancestry is structured genetically.

Jakobsson, M., Scholz, S.W., Scheet, P., Gibbs, J.R., VanLiere, J.M., Fung, H., Szpiech, Z.A., Degnan, J.H., Wang, K., Guerreiro, R., Bras, J.M., Schymick, J.C., Hernandez, D.G., Traynor, B.J., Simon-Sanchez, J., Matarin, M., Britton, A., van de Leemput, J., Rafferty, I., Bucan, M., Cann, H.M., Hardy, J.A., Rosenberg, N.A., Singleton, A.B. (2008). Genotype, haplotype and copy-number variation in worldwide human populations. Nature, 451(7181), 998-1003. DOI: 10.1038/nature06742

Li, J.Z., Absher, D.M., Tang, H., Southwick, A.M., Casto, A.M., Ramachandran, S., Cann, H.M., Barsh, G.S., Feldman, M., Cavalli-Sforza, L.L., Myers, R.M. (2008). Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation. Science, 319(5866), 1100-1104. DOI: 10.1126/science.1153717

Lohmueller, K.E., Indap, A.R., Schmidt, S., Boyko, A.R., Hernandez, R.D., Hubisz, M.J., Sninsky, J.J., White, T.J., Sunyaev, S.R., Nielsen, R., Clark, A.G., Bustamante, C.D. (2008). Proportionally more deleterious genetic variation in European than in African populations. Nature, 451(7181), 994-997. DOI: 10.1038/nature06611

The next edition of the anthropology blog carnival, Four Stone Hearth will be appearing this coming Wednesday, February 27th, over at Archaeoporn, so if you’d like to send something along, here’s the link – submit@fourstonehearth.net

One more from Molecular Biology and Evolution, this time investigating whether or not diversity seen in 280 bases of mtDNA from 886 people from 27 indigenous Americans is localized amongst populations. Or in other words, is the diversity seen in this short segment of mtDNA random or unique to groups?

The paper, “Native South American Genetic Structure and Prehistory Inferred from Hierarchical Modeling of mtDNA,” tells us in fact,

“[the] main discovery is that Eastern South America harbors more genetic variation than has been recognized. We find no evidence that there is increased identity by descent in the East relative to the total for South America. By contrast, we discovered that populations in the Western region, as a group, harbor more identity by descent than has been previously recognized, despite the fact that average identity by descent within groups is lower. In this light, there is no need to postulate separate founding populations for the East and the West because the variability in the East could serve as a source for the Western gene pools.“

Pretty cool how all it takes is a short amount of mtDNA to consider who founded whom.

Lewis, C.M., Long, J.C. (2008). Native South American Genetic Structure and Prehistory Inferred from Hierarchical Modeling of mtDNA. Molecular Biology and Evolution, 25(3), 478-486. DOI: 10.1093/molbev/msm225