Anthropology.net

Almost every biological anthropology text-book I’ve ever looked at has described the adaptations of human populations to the environments they occupy. Examples they give are the short stalky Inuit adapted to conserving heat in cold environments, the long lanky East African nomads adapted to far distant travels, and the barrel chested Peruvian and Tibetans living in low oxygen environments.

Highland Tibet

Little discussion, beyond correlating ecology and physical observation, is given to these. Actually I lie, the physiology of the barrel chested high altitude occupants is given a couple of sentences as well as an elevated oxygen binding capacity without concentrating their blood.

A paper published in Science several days ago tackles this latter issue. A group of scientists looked for unique alleles among Tibet highlanders and discovered 10 unique oxygen-processing alleles. I don’t have full access to the publication, so can’t tell if these genes encode for completely different functioning proteins or are differentially regulated at high altitudes.

All I can derive is that these genes seem to prevent polycythemia, edematous swelling of the lungs and brain, and hypertension of the pulmonary vasculature, which are all complications of high altitude living.  Two of these genes are EGLN1 and PPARA. PPARA is a peroxisome proliferation proteins that also is a leukotriene antagonist. That is interesting because in obstructive conditions like asthama, leukotrienes induce vasospasm and bronchconstriction. EGLN1 is also has an interesting role,

“it is a protein encoded by this gene catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis.”

These two genes were significantly associated with the decreased hemoglobin phenotype that is unique to this highland population.

Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, & Ge R (2010). Genetic Evidence for High-Altitude Adaptation in Tibet. Science (New York, N.Y.) PMID: 20466884

The current issue of the Journal of Neurodevelopmental Disorders has published an open access paper announcing the discovery of a new candidate gene linked to language, KIAA0319. The paper is titled, “Convergent genetic linkage and associations to language, speech and reading measures in families of probands with Specific Language Impairment.”

The gene sits on short arm of Chromosome 6. Through linkage analysis, it was found to be associated with variability in language abilities in a study of children with Specific Language Impairment (SLI) and their family members, as well as with variability in speech and reading abilities. Specific alleles were confirmed with association analysis.

“A total of 322 participants, including 86 probands, 134 siblings, and 102 parents and other relatives were tested from an ongoing longitudinal study of Specific Language Impairment… The significant results cluster in the 5’ region of KIAA0319… In particular, we replicate the associated alleles for rs4504469 (allele C); rs761100 (allele G); rs6935076 (allele T) and rs3756821 (allele A).”

It should be noted that KIAA0319 was already linked to dyslexia in previous studies. But, in this paper, the pleiotropic effects of KIAA0318 alleles on language ability, speech impairments, and text comprehension were correlated.

Rice, M., Smith, S., & Gayán, J. (2009). Convergent genetic linkage and associations to language, speech and reading measures in families of probands with Specific Language Impairment Journal of Neurodevelopmental Disorders DOI: 10.1007/s11689-009-9031-x

Kambiz here. I’m about to start my second term of medical school, which is both exciting and nerve racking. In my summer readings, I came across a medical and anthropological tidbit today that caught my attention: redheads have a lower tolerance for pain. I didn’t know that.  Did you?

Skin pigmentation is one of my favorite topics. We know from previous posts that the melanocortin-1 receptor gene or MC1R affects melanin production and ultimately skin and hair phenotypes. Redheads carry a variant of MC1R which produces a different pigment, called pheomelanin, resulting in freckles, fair skin and ginger hair.

How MC1R receptors affect pain is another story though, one that is not well understood. Aside from the skin MC1R is also expressed in the brain. It could be possible that the redhead allelic variant of the MC1R receptors don’t quite receive the signal transduction of pain reception in the same manner as those with the wildtype receptor. I don’t think I’m gonna become an anthesthesiologist but as someone interested in human genetic variation it is good to acknowledge some phenotypes affect how medicine is delivered. ;-)

Anyways, I don’t have much else to add to this other than to share some interesting information and to let you all know I’m alive but will be crawling under a rock again. Till next time.

The American Journal of Human Genetics has published an article titled, “Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock,” in which a more accurate method of dating ancient human migration, even when no corroborating archaeological evidence exists, is announced.

How does was this done?

The authors started with a sample of 2,000 fully sequenced mtDNA genomes. Not only does this increase the accuracy, but also the precision, ultimately allowing for more narrow temporal ranged. Furthermore, the new method integrates the process of natural selection, which normally skews migration results. In doing so, they authors confirmed that their new methodology works by comparing it against known colonization of Polynesia in the Pacific (approximately 3,000 years ago), and the Canary Islands (approximately 2,500 years ago) extracted from archaeological data.

Aside from confirmation, some more ‘surprising’ results have also been extracted. Last author, Martin B. Richards comments,

“We can settle the debate regarding mankind’s expansion through the Americas. Researchers have been estimating dates from mtDNA that are too old for the archaeological evidence, but our calculations confirm the date to be some 15,000 years ago, around the time of the first unequivocal archaeological remains.

Furthermore, we can say with some confidence that the estimate of humanity’s ‘out of Africa’ migration was around 60-70,000 years ago — some 10-20,000 years earlier than previously thought.”

The press release says that the team has made their  simple calculator freely available on on the University of Leeds website. But I can’t seem to find it, but the supplemental data includes an Excel spreadsheet version of the calculator for you to use and dissect. Anyone got the link to the online calculator?

Pedro Soares, Luca Ermini1, Noel Thomson, Maru Mormina, Teresa Rito, Arne Röhl, Antonio Salas, Stephen Oppenheimer, Vincent Macaulay, & Martin B. Richards (2009). Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock American Journal of Human Genetics

There’s an interesting discussion brewing about on Dienekes’ Anthropology Blog about the ancestral discord between the genetics and craniometric traits of native American populations. I wanted to point it out to all in case you don’t subscribe to Dienekes. The discussion revolves around a rather new PLoS One paper addressing the observation that while native American mtDNA remained relatively static since the Holocene, the cranial morphology of the group has undergone major shifts. The paper is open access and can be found at this link, “Discrepancy between Cranial and DNA Data of Early Americans: Implications for American Peopling.”

Dienekes addresses 3 hypotheses as to why this could be. I generally subscribe to the third hypothesis he mentioned. But in focusing on the paper I have found some concerns about the study sample. Firstly the samples originate only from Argentina. I’m not surprised about this as the researchers are Argentinian scientists, however how can one draw ‘implications for American peopling’ when the sample is confined to 16 individuals from Patagonia and the Pampas? What happened to checking out specimens from Brazil, central America, and the northern territories?

Furthermore, the samples come from a 1,500 year time frame…  starting at 7,800 years ago. We know the earliest migrations to the Americas started 40,000 years ago and people didn’t just make a B-line to Argentina. Populations dispersed. So to make conclusions about Paleoamerican and Amerindian groups based off of 16 skulls from a narrow spatial and temporal window in the peopling of the Americas is flawed, even if these 16 skulls seem to be consistent with morphological and genetic variation patterns interpreted as differences between Paleoamerican and Amerindian groups.

I don’t want this to turn into a time old critique on sample size and distribution analysis. I think we all know that bioarchaeological and paleontological studies also have many reasons to narrow samples. Sometimes it is political, while other times it is based plainly on accessibility to samples as to why a study is narrow. But that doesn’t give anyone an excuse to go ahead and publish it!

Perez, S., Bernal, V., Gonzalez, P., Sardi, M., & Politis, G. (2009). Discrepancy between Cranial and DNA Data of Early Americans: Implications for American Peopling PLoS ONE, 4 (5) DOI: 10.1371/journal.pone.0005746

Many have written how the term ‘junk DNA’ is an imperfect one, and how junk DNA may have a tangential role in evolutionary changes. A new study published in Science visits this topic, specifically focusing on repetitive non-coding sequences in and around promoter regions of the human genome. The authors of this study have published their findings under the title, “Unstable Tandem Repeats in Promoters Confer Transcriptional Evolvability.”

DNA Packaging

The findings concluded that the repeats affect the activity of neighboring genes by way of how tightly the downstream DNA is wrapped around a complex of proteins collectively called a nucleosomes. A nucleosome is one of the half dozen packaging features of the eukaryote genome which allows a genome that is 3 billion base pairs long or 6 feet in length to be squeezed into a tiny little nucleus. About 167 basepairs wrap around one nucelosome. DNA that is more wrapped around a nucleosome is harder to be activated, and thus otherwise non-coding/junk tandem repeats of sequences determine how tightly the local DNA is wrapped around these protein complexes.

The extra cool finding about this paper is that the tandem repeats are very unstable, as you possibly could tell from the title. The authors found out that the number of repeats changes a lot during DNA replication, as if the DNA pol III exonucleases don’t bother proof-reading these areas! These changes affect the local DNA packaging, which in turn alters gene activity. In this way, unstable junk DNA is one of the faster acting mechanisms in altering gene activity with each cellular division.

As an extra step, the researchers conducted a experiment investigating the impact of these tandem repeats on yeast cells. They found out that when a repeat is present near a gene, it is possible to select yeast mutants that show vastly increased activity of this gene. But, when the repeat sequences were removed, this fast evolution was impossible.

So what does this all mean for human evolution? Well, unstable pieces tandem repeats of ‘junk’ non-coding DNA are one of the many ways of regulating gene expression and honing on when a gene’s activity can enable organisms like humans to quickly adapt to changes in their environments.

Vinces, M., Legendre, M., Caldara, M., Hagihara, M., & Verstrepen, K. (2009). Unstable Tandem Repeats in Promoters Confer Transcriptional Evolvability Science, 324 (5931), 1213-1216 DOI: 10.1126/science.1170097

FOXP2 is one of my favorite genes. I studied it extensively while getting my Master’s degree and wrote about it several times on Anthropology.net. For those that do not know much about it, I’ll quickly introduce it. FOXP2 is a transcription factor gene, which means it controls the expression and regulation of many other genes. It is significant in that it is implicated in human language.

I caught news of a new study on FOXP2 today while reading Nicholas Wade’s article in the New York Times about a hot-off-the-press Max Planck study published in Cell on FOXP2. The study comes from Svante Pääbo‘s lab, who created a strain of transgenic mice with the human FOXP2 variant and noted that these mutant mice made whistles that had a slightly lower pitch than ones with the wild-type FOXP2 gene.

The study has been published as an open access paper under the title, “A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice.” There are more findings tucked inside the paper that indicate the impact of the human FOXP2. Aside from the changes in dopamine levels, the most interesting one is the increased axonal and dendritic length of medium spiny neurons in the basal ganglia by 80% when compared to FOXP2^wt. These neurons coordinate the movement and timing of multiple organ systems. Check out the differences for yourself:

Foxp2(hum) Increases the Length of Dendritic Trees

The authors hypothesize on the meaning behind this change in these neurons,

“Currently, one can only speculate about the role these effects may have played during human evolution. However, since patients that carry one nonfunctional FOXP2 allele show impairments in the timing and sequencing of orofacial movements (Alcock etal., 2000,Watkins etal., 2002a), one possibility is that the amino acid substitutions in FOXP2 contributed to an increased fine-tuning of motor control necessary for articulation, i.e., the unique human capacity to learn and coordinate the muscle movements in lungs, larynx, tongue and lips that are necessary for speech (Lieberman, 2006). We are confident that concerted studies of mice, humans and other primates will eventually clarify if this is the case.”

What’s also curious is that the mutant FOXP2 mice don’t seem to have any other effects on other organs, despite the fact that FOXP2 is pretty much ubiquitously expressed all over. It seems like the only manifestations of a human variant showed up in the neuron length and dopamine levels of the brain and ultimately vocalization behaviors. This is an excellent paper which investigates the functional differences of FOXP2, and I recommend you downloading a copy and reading it for yourself.

The Pritchard lab has put up an awesome new interface to query the data from the Human Genome Diversity Project, the HDGP Selection Browser. This is browser is phenomenal. You may have known about a previous iteration, Haplotter, also made by the Pritchard lab, which isn’t too user friendly and restricted to only data from four populations.

SLC24A5 SNP (rs2433354) Distribution Frequencies

The new HDGP Selection Browser integrates over 650,000 SNPs from 968 individuals originating from 52 different populations, making it much more granular data. As Razib also stated, the database is queried via GET, meaning we can hotlink to genes of interest, like SLC24A5: a gene related to skin coloration. The authors also provide a map to view how the certain alleles are geographically distributed. For example, see how this SNP, rs2433354 is spread throughout the world. Humans are really genetically different!

Daniel MacArthur, of Genetic Future, has a really awesome do it yourself post on how to use the database. I recommend you check it out if you’re interested in know how to figure out how populations vary on a gene to gene basis. Also, Daniel explains how to look to see if a certain gene or allele has population-specific selection. I won’t rehash and try to steal his thunder since he did such an excellent job.

I tip my hat to the Pritchard lab for developing such a fine database interface. I’ve been working on making my own database and it is not easy to make such a fluid and well executed application and user interface. You guys really made a stellar tool that I will be using a lot in the future.

The role of copy number variations (CNVs) has been explained before. In 2006 I discussed the identification of 355 CNVs in the chimpanzee genome, later in 2007 a study fished out human lineage-specific CNVs by comparing them to ones found in chimpanzees, and lastly, this year, another study suggested that CNVs may account for much more genetic variation among individuals than we’ve previously thought. This week the journal Genome Research published a paper which is the largest comparison of CNV differences between human and chimpanzee genomes. The authors specifically sought to identifying regions that have been duplicated or lost during evolution of the two lineages.

Colocalization of CNVs and SDs in the human and chimpanzee genomes

The paper, “Copy number variation and evolution in humans and chimpanzees,” reports on using whole genome tilepath microarrays for the high-throughput identification of these chromosomal deletions and duplications. The arrays had 28,708 DNA clones on them and the DNA from 30 unrelated chimpanzees and 30 unrelated people of African ancestry were used in this comparative genomic screening. Why Africans? Well the  genetic diversity in Africans, especially sub-Saharan populations, is comparable to that of Western chimpanzees. In order compare large scale (kilobase) genetic variation, have populations that both exhibit inherit diversity already knocks out one variable.

DNA was isolated and hybridized to the arrays. Experiments were duplicated. CNVs were validated by FISH and PCR. The authors and reported that each individual had an average of 70 to 80 CNVs. CNVs of genes that genes involved in the inflammatory response and cell proliferation – are more commonly duplicated or deleted and also occur in both species very frequently in orthologous genomic regions, suggesting a tight association to homologous intrachromosomal segmental duplications. Some examples are APOL1, APOL4, CARD18, IL1F7, IL1F8 and are completely deleted from chimp genome. In humans, APOL1 is involved in immune response to the Trypanosoma brucei parasite, transmitted by the tsetse fly, that causes sleeping sickness. IL1F7 and CARD18 play a role in regulating inflammation: therefore, there must be different regulations of these processes in chimpanzees.

Of particular interest is the identification of a CNV: CCL3L1. When compared to chimpanzees, humans have far fewer copies of this gene. Deletions in CCL3L1 have been associated with increased susceptibility to HIV infection. Another gene, TBC1D3, involved in cell proliferation, was reduced in number in chimpanzee compared to human. On average, there were eight copies in humans sampled, but apparently only one in all chimpanzees and this difference. This difference is argued to have been driven by selection.

SNPs are usually the goto comparative genomic marker for most comparative genetic studies. In this situation CNVs were the star. CNVs can have more impactful phenotypic effects than SNPs — where a SNP may alter the shape a final protein makes or alter the promoter sequence, duplications of a gene can lead to more proteins produced. Deletions in copy numbers can also down size the amount of protein produce, affecting the biochemical pathways the product is involved in. So are CNVs more important thant SNPs or other forms of genetic variation? No. They are one of the many structural elements that need to be studied to completely understand the variomes present within human populations and between humans and related species.

G. H. Perry, F. Yang, T. Marques-Bonet, C. Murphy, T. Fitzgerald, A. S. Lee, C. Hyland, A. C. Stone, M. E. Hurles, C. Tyler-Smith, E. E. Eichler, N. P. Carter, C. Lee, R. Redon (2008). Copy number variation and evolution in humans and chimpanzees Genome Research, 18 (11), 1698-1710 DOI: 10.1101/gr.082016.108

One of the pieces to appear in the latest Science is Constance Holden’s synopsis of the core issues discussed at last week’s meeting of the National Human Genome Research Institute: defining geographic populations, handling interpretations of race (especially as as a sociopolitical term), and phrasing results of population genetic studies.

I paid cursory attention to the etymological aspects of the piece. Yes, I know Amerindian isn’t how some Native Americans want to be identified as, and there are some problems with figuring out where European populations end and where Asian populations begin. But I’m hopeful, as more individual genomes are sequenced and released, that genetic patterns can better define populations than cultural and geographic categories have in the past. We don’t necessarily have to rephrase terms or agree on new ones, but can possibly use biological terms, such as allele frequencies, as defining characteristics of populations.

Holden also reviews a discussion on interpretations of fitness — i.e. how some of the public may interpret Carlos Bustamante’s recent Nature paper, where he concluded that European-Americans had more deleterious gene mutations than African-Americans. Does that mean there’s some sort of superiority? No, but that doesn’t mean the public won’t interpret it like that. Should scientists hold back on their reporting their results or sugar coat them just to prevent the public from over analyzing them? I don’t think so.

The must read part of this news piece, especially for anyone news piece for anyone interested in the current state of population genetics and molecular anthropology, is the heated debate between Bruce Lahn and Celeste Condit, a professor of speech communication at the University of Georgia, Athens. Bruce Lahn, as you may know reported 4 years ago that selection in mutations of two genes (ASPM & microcephalin) regulating brain development is more common in Eurasians than in Africans. Condit argued that Lahn’s results have a political message embedded, a common mistake that many uneducated critics of population genetics repeat. We’ve had similiar misconceptions raised on Anthropology.net. Lahn retored back that some…

“are almost like creationists” in their unwillingness to acknowledge that the brain is not exempt from selection pressures.”

Oh snap! The whole meeting didn’t seem to be fruitless though, most agreed that suppressing freedom of reporting results as they are observed in the name of political correctness is not conduicive to the scientific method.

C. Holden (2008). PERSONAL GENOMICS: The Touchy Subject of ‘Race’ Science, 322 (5903), 839-839 DOI: 10.1126/science.322.5903.839a