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

Razib has chimed in on the latest piece of research to come from John Lukacs, “Fertility and Agriculture Accentuate Sex Differences in Dental Caries Rates,” published in Current Anthropology. Throughout time, women have had more cavities on average than men. I’ve explained how cavities are formed in a previous post.  Diet change and sexual division of labor have been suggested to be the dominant forces at play. With the Neolithic revolution, the human diet and lifestyle was dramatically revamped. With steady food sources, people reproduced faster and populations boomed.

Lukacs did a comprehensive review of records of the frequencies of dental cavities in both prehistoric and living human populations in his paper. His sample included teeth from people of Euro-American ancestry, and from Africa, teeth from Guinea-Bissau, Madagascar, and Niger… from Asia, he covered China and Taiwanese aboriginals.

He concluded that the increased sedentary lifestyle and fertility increased the demands on the female reproductive system, which in turn intensified the negative impacts of dietary change on oral health. of women He attributes the increased rates of dental caries in females to three factors:

• Female sex hormones, like estrogen, significantly impact cavity formation. Estrogen is produced by the placenta throughout a pregnancy and the levels increase steadily until birth.
• Females produce less saliva than men. Saliva has two important components, enzymes like amylase, that begin break down of complex sugars. If these sugars aren’t broken down, microbes in the mouth consume them and as a biproduct release acids that break down the enamel of the tooth. Saliva also has another component, antibodies and phagocytes that attack the very microbes that cause cavities.
• Women crave high-energy, sweet foods during the third trimester which we all know are promotes cavities and dental decay.

So ultimately female physiology combined with the the changes in diet and increased feritlity are the reasons why women have more cavities than men. Razib mentions that with increased fertility comes a reciprocal increase infant mortality, especially because the agricultural revolution increased communicable diseases. He concludes that hunter-gatherer infants are far more likely to reach reproductive age than infants of an agriculturalist.

But I disagree. Despite the recent popularity of the paleo-diet, the real hunter gatherer lifestyle is not easy. Many hunter gatherer societies have erratic sources of nutrition, very few have regular caloric intakes. John Hawks explained that among hunter gatherers, like the Hiwi, only 43% of the adults were expected to see the age of 30. Furthermore, many hunter gatherer cultures also have food taboos which dictate the diets of females. For example, Australian aboriginal societies restrict protein and fat foods for pregnant and lactating women. Similar traditions exist in Africa too. In Athapaskan societies, females at menarche cannot eat fresh meat.

Women who do not consume many calories, reach menarche at an older age and become amenorrheic — irregularly menstruate. If and when they do have a child, they are often of low birth weight, and the child has a higher risk of dying because they have little to no fat reserves. They consume inadequate amounts of nutrition since the mothers cannot make insufficient amounts of milk. All of which influences birth spacing significantly.

Despite the increased probability of cavities, the Neolithic revolution has generally been a good thing for women and children.

John R. Lukacs (2008). Fertility and Agriculture Accentuate Sex Differences in Dental Caries Rates Current Anthropology, 49 (5), 901-914 DOI: 10.1086/592111

Razib shares with us an overview of a new PLoS One paper which investigated the selection of an allele of alcohol dehydrogenase found in high frequency in some East Asian peoples. I gotta hand it to him for the snarky title of his post. Alcohol dehydrogenase is an enzyme that functions to break down alcohols which could otherwise be toxic. There are many classes of alcohol dehydrogenases. The specific allele in this study, ADH1b*47His, is associated with a decrease in the risk of alcoholism. How? These class of alcohol dehydrogenase (ADH) alleles expedite the metabolism of alcohols. Alleles that metabolize alcohols slower, such as the ADH2 and ADH3 variants, are associated with alcoholics.

The observation that ADH1b*47His is found in high frequencies in some East Asian populations have got Hui Li and coauthors curious to figure out if there has been some sort of selection to confer this decrease of alcoholism allele to be present in many peoples. They recently published their study in the free and open access journal, PLoS One. The research behind this paper, “Ethnic Related Selection for an ADH Class I Variant within East Asia,” involved looking at 30 different SNPs in the ADH gene of 24 different populations. It was observed that the unique ADH1b alleles correlated directly with ethnic groups, which I think is completely fascinating from an anthropological perspective.

In their population screen, it was observed that the ADH1b*47His allele is found highest in Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian people. Further, investigation of the ADH gene revealed that ADH1b*47His is actually a SNP that falls smack dab in the regulatory region of ADH. Regulatory regions are portions of a gene where promoters, inhibitors, and other transcription factors bind preferentially. Any alteration of these regions of genes ultimately effects how much product is made.

As Razib highlighted, the authors think that the real focus of selection may be the regulatory region. Well, no duh, the derived promoter allele probably increased expression levels of the enzyme and with more enzyme available, that ultimately helped people process alcohol more efficiently and faster. Clearly there’s a selective advantage to having more enzymes available to oxidize toxic agents. But the authors are a bit conservative in saying that detoxifying alcohol is primary reason why ADH1b*47His is present in high frequency in East Asian people. In fact, they suggest that ADH1 alleles have something to do with cancer, infectious diseases, etc. Makes sense, I mean these enzymes are detoxifying agents.

I know this post was heavy on population genetics, biochemistry and some physiology. I have to review that to some extent to give a background on ADH. I do want to point out again that this study yet again shows us that there are genetic differences between ethnic groups. Be it in ADH, or any other ancestry inherited marker, ethnic populations do exhibit some clearly definable genetic differences.

Li, H., Gu, S., Cai, X., Speed, W.C., Pakstis, A.J., Golub, E.I., Kidd, J.R., Kidd, K.K., Harpending, H. (2008). Ethnic Related Selection for an ADH Class I Variant within East Asia. PLoS ONE, 3(4), e1881. DOI: 10.1371/journal.pone.0001881

Dopamine is a fundamental neurotransmitter and hormone. You may know it as one of the neurotransmitters associated with the limbic system, being released during eating and sex, which causes a sensation of pleasure. But it is more than just a hedonistic chemical, actually many of the functions of the brain are dependent on dopamine. Memory, attention and problem solving revolve around dopamine to control the flow of information from other areas of the brain to the frontal lobes. As a hormone, dopamine acts a precursor to noradrenaline and adrenaline and thus increases heart rate and blood pressure during sympathetic nervous system response.

For this purposes of this post, dopamine is an important neurotransmitter that regulates behavioral responses. In brains of people with deficiencies in dopamine levels, attention deficit hyperactivity disorder is an all too common diagnosis. Low levels of dopamine also cause social withdrawal, apathy, and anhedonia. Furthermore, social anxiety is associated with neurons that are unable to bind dopamine. When dopamine is unregulated and in excess, extraversion or gregarious and assertive behaviors are observed.

Before I jump deep into the post, let me first run down some neuron physiology. Without an understanding about how neurons and their associated chemicals function, it’s hard to comprehend how a mutation in any one of the components leads to neurological, cognitive and behavioral disorders. Neurons are specialized cells of the nervous system that are depolarizable and this ability allows signal to be transduced. Signals come in two forms, graded or action potentials. I won’t get into the nitty gritty of how potentials are formed but just know that once graded potentials reach a threshold, an action potential is generated that rushes down the axon of a neuron. Action potentials are an all or none response.

The action potential travels down axon to the presynaptic terminal where it causes channel proteins to open. The presynaptic terminals contain vesicles chock full of neurotransmitters. The opening of channel proteins influences the vesicles full of neurotransmitters to fuse with the presynaptic membrane. The neurotransmitter is released into the space between the presynaptic membrane called the synaptic cleft and it targets its reciprocal receptor on the postsynaptic membrane of the next neuron. The effect of the neurotransmitter on the postsynaptic membrane will depend on the nature of the neurotransmitter, the nature of the postsynaptic receptors, and whether the postsynaptic ion channels are voltage-gated or chemically-gated. In dopamine’s case, it is hypothesized to provide a teaching signal to parts of the brain responsible for acquiring new behavior.

To clean up the neurotransmitters, specialized proteins called transporters function to re-uptake the bound neurotransmitters back into the neuron. I imagine them as vacuums. In dopamine’s case, a specific transporter exits, and is called the dopamine transporter… but we’ll be calling it DAT. Since DAT cleans up dopamine, and inactivates its function, it is critical in regulating (stopping) the network of effects dopamine is responsible for. Any mutation in the DAT gene that also changes the amino acid composition of the transporter ultimately affects the ability of the protein to stop dopamine’s effects.

In humans, the DAT gene is fairly large, around 64,000 base pairs long and consists of 15 exons. Evidence for the associations between DAT and dopamine related disorders have come from a genetic polymorphisms studies of the DAT gene. Currently mutations in DAT are implicated in a number of dopamine related disorders such as attention deficit hyperactivity disorder, bipolar disorder, clinical depression, and alcoholism.

Because DAT modulates the extent of dopamine activity on the receptor, it becomes an excellent candidate to study how variants of DAT effect behavior and ultimately if the variants offer an selective advantage. In what I consider a really awesome paper in the journal, Molecular Biology and Evolution, a half dozen geneticists at the University of Pittsburg, studied DAT for sequence variation in populations of two different macaque species and humans. They calculated the extent of the different combinations of DAT alleles in their populations that would be more or less frequent than what’s expected from a random formation of haplotypes. The amount of non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium, which is the basically the probability to find same set of alleles at two or more loci. The key word here is non-random. In order to study whether or not a mutation in the DAT gene has any affects on survivability, we need to figure out the random variants from the ones that are seemingly selected for.

The paper, “Sequence Variation in the Primate Dopamine Transporter Gene and Its Relationship to Social Dominance,” tells us how they went about doing that. First they sampled about 760 monkeys but only 23 humans. They designed primers for the DAT gene and each exon was sequenced. That’s a lot of sequencing, if my estimations are correct, that’s around 12,000 different reactions. But I don’t know that for sure. Either way, 78 polymorphisms were identified but only two functional variants were linked to high social rank. Social rank was observed through the level of dominance (aggressive, use of attack gestures, actions, and vocalizations more frequently, and consistently defeat individuals of lower rank).

What I’m kinda iffy on is how they identified the variants, located in 5′ UTR, if they only sequenced the exons. Regardless, they realized that heterozygous individuals, with one copy of the minor 5′ UTR allele, were more likely to be of subordinate rank than those who were homozygous for the major allele. In other words,

“the odds that a subordinate individual possesses at least one copy of the minor allele… are one and a half to nearly twice the odds of it being homozygous… In contrast, subordinates were significantly less likely to be heterozygous than homozygous.”

The two DAT 5′ UTR variants fall at a putative transcription factor–binding site. They don’t get deep into a discussion on how the variants affect the transcription factor-binding site (other than the minor allele abolishes the core sequence) nor what the putative transcription factor that binds to it, which would be two a really cool study in itself. If one could take the 2 variants and compare how levels of gene expression vary, then we can get an idea if the homozygous alleles allow for less DAT to be transcribed and ultimately allow for more dopamine to float around causing extraversion and socially dominant behavior. But they do identify NFAT as a regulator,

“…these transcription factors thus play a crucial role in shaping long-term changes in neuronal function. They are also sensitive to secondary messenger systems activated by brain-derived neurotrophic factor (BDNF) which regulates expression of the dopamine D3 receptor. It is thus possible that NFAT and/or BDNF also modulates expression of DAT. “

I consider this study extremely enlightening in understanding the biological mechanisms behind primate social behavior and ultimately evolution. See we have behavior, social dominance, that for the most part we think has evolutionary significance and has something to do with dopamine and the regulation of this neurotransmitter. In order to figure out if the two are linked, one needs to correlate that a variation in any portion of the gene that regulates dopamine activity (DAT) is linked to a heterozygote or homozygote state.

In this case, Robert Ferrell and his lab identified a difference in an area slightly upstream of DAT that controls the rate it is transcribed in macaques. By looking at the variants in each individual and the observations of the social behavior, his lab figured out heterozygous individuals we’re as bossy. Pretty amazing, if you ask me. But this putative binding site is not found in the homologous region of human DAT, which is also really interesting! Has social dominance by way of the dopamine network not been positively selected or lost in the human lineage? Or have we humans found another biochemical pathway to influence dominant behavior?