Sex, Microcephalin, and Neanderthals

The publication last month of a draft sequence of the Neanderthal genome stoked quite a bit of excitement, much of it over the question of whether Neanderthals and anatomically modern humans ever indulged in hanky-panky. The query I want to focus on here is more specific. It concerns how modern humans acquired a particular allele for a particular gene. Did we get it from a Neanderthal during a romantic evening?

The general question of human-Neanderthal liaisons has long been hotly contended. In 1999, debate over the ancient skeleton of a four-year-old found in Portugal—some thought the child was a stocky modern human, others thought it was a Neanderthal-human hybrid—burst out of the pages of Proceedings of the National Academy and into an email flame war. The team that produced the draft Neanderthal genome think their sequence suggests an answer. The genomes of modern humans and Neanderthals are nearly identical, but those of non-African modern humans appear to be more nearly identical to Neanderthals than those of African modern humans. The simplest explanation is that some of the first modern humans to leave Africa paused during their travels to spend an evening or two around a Neanderthal campfire.

The particular allele some researchers have suspected was acquired by modern humans via such a tryst is a version of the gene for microcephalin. Microephalin is a protein made in a variety of tissues, including the fetal brain during the production of neurons. It appears to play a role in the cellular response to DNA damage. It takes its name from the fact that people homozygous for loss-of-function mutations have primary microcephaly, a condition characterized by a small but otherwise structurally normal brain.

Microcephalin caught the attention of evolutionary biologists in 2004, when two groups published analyses indicating that the gene for it accumulated non-synonymous mutations at a high rate during the evolution of the great apes. Non-synonymous mutations alter the sequence of amino acids in the encoded protein. A high rate of non-synonymous evolution suggests that natural selection has favored changes in protein structure and/or function. Perhaps microcephalin is one of the proteins whose evolution endowed great apes, including humans, with big brains.

In 2005 a team led by Bruce Lahn reported an analysis of allelic variation for the microcephalin gene among present-day humans. Broadly speaking, humans carry two alleles. The key difference between them is a single nucleotide substitution (G vs. C) that alters the amino acid encoded at position 314 in the protein. The ancestral allele has a G and encodes aspartate; the derived allele has a C and encodes histidine. This polymorphism is known as G37995C. The global frequency of the ancestral G allele is about 30%, while the frequency of the derived C allele is about 70%.

Among present-day humans, researchers have been unable to find any associations between G37995C genotype and brain size. Nor is there any detectable association between G37995C genotype and intelligence. Curiously, there does seem to be an association between the microcephalin allele frequency in a population and whether the individuals in the population speak a tonal language. The higher the frequency of the C allele, the less likely it is that the language will be tonal.

Copies of the C allele are all quite similar to each other, but they are not all identical. It appears that the C allele arose just once, as the result of a unique mutation, and that additional mutations have since created minor variants of the allele. Using a technique similar to the one students learn in SimBiotic's HIV Clock lab, Lahn's team estimated that the most recent common ancestor of extant copies of the C allele lived about 37,000 years ago, give or take a generous margin of error. The C allele is thus fairly young, but has attained a high frequency. Lahn and colleagues argue that the best explanation is that the novel allele has been favored by natural selection, an interpretation they have defended against critics who have held that scenarios involving genetic drift are also plausible. Precisely why the novel allele might have been favored by selection, given that its only known correlation with phenotype involves language tonality, is anybody's guess. Another unsolved mystery is that the frequency of the novel C allele is much higher in non-African populations than it is in African populations.

In 2006 Lahn and colleagues published a more detailed analysis of the diversity and history of human microcephalin alleles. The most recent common ancestor of extant copies of the G allele lived about 990,000 years ago. The most recent common ancestor of the G allele and the C allele lived roughly 1.7 million years ago. Lahn's team offered and intriguing, if somewhat salacious, explanation for the patterns in their data. Perhaps the novel C allele first arose, not in modern humans, but in a now extinct relative such as Neanderthals. Then, roughly 37,000 years ago, modern humans aquired the allele via a mixed mating. For reasons still unknown, the C allele proved advantageous, at least outside of Africa, and has therefore risen to high frequency.

Last month, a team led by David Caramelli demonstrated the feasibility of testing this hypothesis by doing something that just a few years ago would have sounded like science fiction. They genotyped a Neanderthal for the G37995C polymorphism. The individual they examined lived some 50,000 years ago in what is now Italy. He or she carried two copies of the ancestral G allele. In other words, if we humans got the novel C allele by trysting with a Neanderthal, this particular individual was not the lover in question.

Of course, one data point isn't much evidence. It is entirely possible that Neanderthal populations, like those of modern humans, harbored both microcephalin alleles. But more data are already accumulating. The team that produced the draft Neanderthal genome also failed to find the C allele. Until a copy of the C allele turns up in an archaic human, the exotic romance hypothesis for where it came from will become less plausible with each negative result.

Sources:

The report on the draft sequence of the complete Neanderthal genome and its similarities to the genomes of various modern humans is: Green, R. E., J. Krause et al. 2010. A draft sequence of the Neandertal genome. Science 328: 710–722.

The debate over the skeleton of the ancient child began with a report interpreting it as a human-Neanderthal hybrid: Duarte, C., J. Mauricio et al. 1999. The early Upper Paleolithic human skeleton from the Abrigo do Lagar Velho (Portugal) and modern human emergence in Iberia. Proceedings of the National Academy of Sciences, USA 96: 7604–7609. The report was accompanied by a scathing commentary: Tattersall, I. and J. H. Schwartz. 1999. Hominids and hybrids: the place of Neanderthals in human evolution. Proceedings of the National Academy of Sciences, USA 96: 7117–7119. The subsequent degeneration of the conflict is described briefly in: Holden, C., ed. 1999. Random Samples: Patrimony Debate Gets Ugly. Science 285: 195.

For a review of where microcephalin is made and what it does, see Online Mendelian Inheritance in Man.

For a review of primary microcephaly and the genes associated with the condition, see: Woods, C. G., J. Bond, and W. Enard. 2005. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. American Journal of Human Genetics 76: 717–728.

The two reports of high rates of non-synonymous evolution in the microcephalin gene during the evolution of great apes are: Evans, P. D., J. R. Anderson et al. 2004. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Human Molecular Genetics 13: 1139–1145; and Wang, Y. Q. and B. Su. 2004. Molecular evolution of microcephalin, a gene determining human brain size. Human Molecular Genetics 13: 1131–1137.

The report on allelic varition by Bruce Lahn's team is: Evans, P. D., S. L. Gilbert et al. 2005. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309: 1717–1720.

For the lack of association between G37995C genotype and brain size, see: Woods, R. P., N. B. Freimer et al. 2006. Normal variants of Microcephalin and ASPM do not account for brain size variability. Human Molecular Genetics 15: 2025–2029; Dobson-Stone, C., J. M. Gatt et al. 2007. Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort. Neuroimage 37: 394–400. For the lack of association between G37995C genotype and intelligence, see: Mekel-Bobrov, N., D. Posthuma et al. 2007. The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence. Human Molecular Genetics 16: 600–608. For the relationship between G37995C allele frequency and language tonality, see: Dediu, D. and D. R. Ladd. 2007. Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin. Proceedings of the National Academy of Sciences 104: 10944–10949.

For a critique of the idea that the derived allele of microcephalin rose to high frequency as a result of selection, and an exploration of the alternative hypothesis that the allele rose to high frequency by genetic drift, see: Currat, M., L. Excoffier et al. 2006. Comment on "Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens" and "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans." Science 313: 172a. For the response by Lahn's team see: Mekel-Bobrov, N., P. D. Evans et al. 2006. Response to comment on “Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens” and “Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans." Science 313: 172b.

The paper in which Lahn and colleagues suggested hybridization between humans and Neanderthals as a plausible explanation for their data on microcephalin alleles is: Evans, P. D., N. Mekel-Bobrov et al. 2006. Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage. Proceedings of the National Academy of Sciences 103: 18178–18183.

Caramelli and colleagues' demonstration that Neanderthal remains can be genotyped for the G37995C polymorphism is: Lari, M., E. Rizzi et al. 2010. The microcephalin ancestral allele in a Neanderthal individual. PLoS ONE 5: e10648.

A note on spelling:

Both "Neanderthal" and "Neandertal" are accepted as correct. For an explantion see TalkOrigins. In the most recent edition of my book we used "Neandertal," I guess because the copy editor prefers it. Lately I've decided I favor "Neanderthal" because it matches the latin name, Homo neanderthalenisis. Or—yet another can of worms—is it Homo sapiens neanderthalensis?