Multiple independent origins of sex chromosomes in amniotes.
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Amnion↗
Biomedical subjects
Eric J Vallender
Publications and source records attributed to Eric J Vallender.
Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage.
At the center of the debate on the emergence of modern humans and their spread throughout the globe is the question of whether archaic Homo lineages contributed to the modern human gene pool, and more importantly, whether such contributions impacted the evolutionary adaptation of our species. A major obstacle to answering this question is that low levels of admixture with archaic lineages are not expected to leave extensive traces in the modern human gene pool because of genetic drift. Loci that have undergone strong positive selection, however, offer a unique opportunity to identify low-level admixture with archaic lineages, provided that the introgressed archaic allele has risen to high frequency under positive selection. The gene microcephalin (MCPH1) regulates brain size during development and has experienced positive selection in the lineage leading to Homo sapiens. Within modern humans, a group of closely related haplotypes at this locus, known as haplogroup D, rose from a single copy approximately 37,000 years ago and swept to exceptionally high frequency (approximately 70% worldwide today) because of positive selection. Here, we examine the origin of haplogroup D. By using the interhaplogroup divergence test, we show that haplogroup D likely originated from a lineage separated from modern humans approximately 1.1 million years ago and introgressed into humans by approximately 37,000 years ago. This finding supports the possibility of admixture between modern humans and archaic Homo populations (Neanderthals being one possibility). Furthermore, it buttresses the important notion that, through such adminture, our species has benefited evolutionarily by gaining new advantageous alleles. The interhaplogroup divergence test developed here may be broadly applicable to the detection of introgression at other loci in the human genome or in genomes of other species.
Adaptation, Biological↗
A primate-specific acceleration in the evolution of the caspase-dependent apoptosis pathway.
Programmed cell death, or apoptosis, plays an essential role in mammalian development, especially the development of the nervous system. Here, we systematically examine the molecular evolution of the mammalian intrinsic apoptosis program. We divided the program into its several constituent pathways and examined the evolution of each pathway in diverse mammalian taxa spanning primates, rodents and carnivores. We observed that genes involved in the caspase-dependent apoptosis pathway stood out in several ways. First, these genes display an accelerated rate of protein sequence evolution in primates relative to rodents or carnivores. Secondly, this acceleration is most pronounced along the lineage leading to humans, and it is associated with signatures of positive selection. Finally, several genes in this pathway, including APAF1, CASP9 and CASP3, have been shown to be associated with dramatic defects in neuronal cell number and brain size when mutated in mice. These observations suggest the possibility that evolutionary changes in the caspase-dependent apoptosis pathway may have contributed to brain evolution in primates and humans. Our results also lend further support to the hypothesis that genes regulating brain size during development might have played a particularly important role in transforming brain size during evolution.
Animals↗
SPEED: a molecular-evolution-based database of mammalian orthologous groups.
MOTIVATION: The abundance of nucleotide sequence information available has expanded horizons of inquiry for molecular evolution; however, the full potential of whole-genome analysis has not been realized because of inadequate tools. Here, we present one of the first toolkits to aid multidisciplinary high-throughput analysis. SUMMARY: SPEED was created to integrate molecular evolutionary data with existing genetic resources and provide a straightforward user interface to 17,352 orthologous gene groups, containing representatives from eight mammalian species and an avian outgroup. AVAILABILITY: See http://bioinfobase.umkc.edu/speed/ for access.
Algorithms↗
Systematically assessing the influence of 3-dimensional structural context on the molecular evolution of mammalian proteomes.
The 3-dimensional (3D) structural context of amino acid residues in a protein could significantly impact the level of selective constraint on the residues. Here, by analyzing 767 mammalian proteins, we systematically investigate how various 3D structural contexts influence selective constraint. The structural contexts we examined include solvent accessibility, secondary structure, and intramolecular residue-residue interactions. Through this analysis, we offer quantitative information on how 3D structural contexts affect the level of selective constraint.
Amino Acids↗
Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates.
Sonic Hedgehog (SHH) is one of the most intensively studied genes in developmental biology. It is a highly conserved gene, found in species as diverse as arthropods and mammals. The mammalian SHH encodes a signaling molecule that plays a central role in developmental patterning, especially of the nervous system and the skeletal system. Here, we show that the molecular evolution of SHH is markedly accelerated in primates relative to other mammals. We further show that within primates, the acceleration is most prominent along the lineage leading to humans. Finally, we show that the acceleration in the lineage leading to humans is coupled with signatures of adaptive evolution. In particular, the lineage leading to humans is characterized by a rampant and statistically highly non-random gain of serines and threonines, residues that are potential substrates of post-translational modifications. This suggests that SHH might have evolved more complex post-translational regulation in the lineage leading to humans. Collectively, these findings implicate SHH as a potential contributor to the evolution of primate- or human-specific morphological traits in the nervous and/or skeletal systems and provide the impetus for additional studies aimed at identifying the primate- or human-specific functions of this key development gene.
Animals↗
Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.
Primary microcephaly is a developmental defect of the brain characterized by severely reduced brain size but an absence of other overt abnormalities. Mutations in several loci have been linked to primary microcephaly. The underlying genes for two of these were recently identified as CDK5RAP2 and CENPJ. Here, we focus on CDK5RAP2 and show that the protein evolutionary rate of this gene is significantly higher in primates than rodents or carnivores. We further show that the evolutionary rate within primates is particularly high in the human and chimpanzee terminal branches. Thus, the pattern of molecular evolution seen in CDK5RAP2 appears to parallel, at least approximately, that seen in two other previously identified primary microcephaly genes, microcephalin and ASPM. We also briefly discuss CENPJ, which similarly exhibits higher rate of protein evolution in primates as compared to rodents and carnivores. Together, the evolutionary patterns of all four presently known primary microcephaly genes are consistent with the hypothesis that genes regulating brain size during development might also play a role in brain evolution in primates and especially humans.
Animals↗
Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.
The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.
Adaptation, Biological↗
Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.
The gene ASPM (abnormal spindle-like microcephaly associated) is a specific regulator of brain size, and its evolution in the lineage leading to Homo sapiens was driven by strong positive selection. Here, we show that one genetic variant of ASPM in humans arose merely about 5800 years ago and has since swept to high frequency under strong positive selection. These findings, especially the remarkably young age of the positively selected variant, suggest that the human brain is still undergoing rapid adaptive evolution.
Adaptation, Biological↗
A highly unexpected strong correlation between fixation probability of nonsynonymous mutations and mutation rate.
Under prevailing theories, the nonsynonymous-to-synonymous substitution ratio (i.e. K(a)/K(s)), which measures the fixation probability of nonsynonymous mutations, is correlated with the strength of selection. In this article, we report that K(a)/K(s) is also strongly correlated with the mutation rate as measured by K(s), and that this correlation appears to have a similar magnitude as the correlation between K(a)/K(s) and selective strength. This finding cannot be reconciled with current theories. It suggests that we should re-evaluate the current paradigms of coding-sequence evolution, and that the wide use of K(a)/K(s) as a measure of selective strength needs reassessment.
Animals↗
The X chromosome: not just her brother's keeper.
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Biological Evolution↗
Accelerated evolution of nervous system genes in the origin of Homo sapiens.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, we examined the evolution of genes involved in diverse aspects of nervous system biology. We found that these genes display significantly higher rates of protein evolution in primates than in rodents. Importantly, this trend is most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution is most prominent in the lineage leading from ancestral primates to humans. Thus, the remarkable phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. In addition to uncovering broad evolutionary trends, our study also identified many candidate genes--most of which are implicated in regulating brain size and behavior--that might have played important roles in the evolution of the human brain.
Animals↗
Positive selection on the human genome.
Positive selection has undoubtedly played a critical role in the evolution of Homo sapiens. Of the many phenotypic traits that define our species--notably the enormous brain, advanced cognitive abilities, complex vocal organs, bipedalism and opposable thumbs--most (if not all) are likely the product of strong positive selection. Many other aspects of human biology not necessarily related to the 'branding' of our species, such as host-pathogen interactions, reproduction, dietary adaptation and physical appearance, have also been the substrate of varying levels of positive selection. Comparative genetics/genomics studies in recent years have uncovered a growing list of genes that might have experienced positive selection during the evolution of human and/or primates. These genes offer valuable inroads into understanding the biological processes specific to humans, and the evolutionary forces that gave rise to them. Here, we present a comprehensive review of these genes, and their implications for human evolution.
Genome, Human↗
Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size.
The defining process in the evolution of primates and particularly humans is the dramatic expansion of the brain. While many types of genes could potentially contribute to this process, genes that specifically regulate brain size during development may be especially relevant. Here, we examine the evolution of the microcephalin gene, whose null mutation in humans causes primary microcephaly, a congenital defect characterized by severe reductions in brain size without other gross abnormalities. We show that the evolution of microcephalin's protein sequence is highly accelerated throughout the lineage from simian ancestors to humans and chimpanzees, with the most pronounced acceleration seen in the early periods of this lineage. We further demonstrate that this accelerated evolution is coupled with signatures of positive selection. Statistical analysis suggests that about 45 advantageous amino acid changes in microcephalin might have fixed during the 25-30 million years of evolution from early simian progenitors to modern humans. These observations support the notion that the molecular evolution of microcephalin may have contributed to brain expansion in the simian lineage leading to humans. We have recently shown that ASPM, another gene linked to primary microcephaly, experienced strong positive selection in the ape lineage leading to humans. We therefore propose that genes regulating brain size during development may have the general propensity to contribute to brain evolution in primates and particularly humans.
Animals↗
Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans.
A prominent trend in the evolution of humans is the progressive enlargement of the cerebral cortex. The ASPM (Abnormal spindle-like microcephaly associated) gene has the potential to play a role in this evolutionary process, because mutations in this gene cause severe reductions in the cerebral cortical size of affected humans. Here, we show that the evolution of ASPM is significantly accelerated in great apes, especially along the ape lineages leading to humans. Additionally, the lineage from the last human/chimpanzee ancestor to humans shows an excess of non-synonymous over synonymous substitutions, which is a signature of positive Darwinian selection. A comparison of polymorphism and divergence using the McDonald-Kreitman test confirms that ASPM has indeed experienced intense positive selection during recent human evolution. This test also reveals that, on average, ASPM fixed one advantageous amino acid change in every 300,000-400,000 years since the human lineage diverged from chimpanzees some 5-6 million years ago. We therefore conclude that ASPM underwent strong adaptive evolution in the descent of Homo sapiens, which is consistent with its putative role in the evolutionary enlargement of the human brain.
Adaptation, Biological↗
How mammalian sex chromosomes acquired their peculiar gene content.
It has become increasingly evident that gene content of the sex chromosomes is markedly different from that of the autosomes. Both sex chromosomes appear enriched for genes related to sexual differentiation and reproduction; but curiously, the human X chromosome also seems to bear a preponderance of genes linked to brain and muscle functions. In this review, we will synthesize several evolutionary theories that may account for this nonrandom assortment of genes on the sex chromosomes, including 1) asexual degeneration, 2) sexual antagonism, 3) constant selection, and 4) hemizygous exposure. Additionally, we will speculate on how the evolution of sex-chromosome gene content might have impacted on the phenotypic evolution of mammals and particularly humans. Our discussion will focus on the mammalian sex chromosomes, but will cross reference other species where appropriate.
Animals↗
Diverse fates of paralogs following segmental duplication of telomeric genes.
The telomeric region of chromosome 9p is paralogous to the pericentromeric regions of chromosome 9 as well as to 2q13, the site of an ancestral telomere-telomere fusion. These paralogous regions span approximately 200 kb and contain seven transcriptional units, including the previously identified CBWD, FOXD4, PGM5, F379, CXYorf1, and two human Unigene clusters, Hs.115173 and Hs.189160. Within these gene duplicates, the number of expressed paralogous loci varies, from one in PGM5 to all three in CBWD and Hs.115173. FOXD4 shows the most dramatic changes among its paralogs. Two independent insertion/deletion changes created four different carboxy ends of these intronless genes, two of which are within the 2q13 locus. A comparison of KA/KS values among functional paralogs shows these genes evolved rapidly in primates. This study shows the importance of paralogous regions in the generation of transcriptional diversity and highlights the significance that large-scale telomeric duplication may play in this process.
Animals↗
Effects of chromosomal rearrangements on human-chimpanzee molecular evolution.
Many chromosomes are rearranged between humans and chimpanzees while others remain colinear. It was recently observed, based on over 100 genes, that the rates of protein evolution are substantially higher on rearranged than on colinear chromosomes during human-chimpanzee evolution. This finding led to the conclusion, since debated in the literature, that chromosomal rearrangements had played a key role in human-chimpanzee speciation. Here we re-examine this important conclusion by employing larger a data set (over 7000 genes), as well as alternative analyses. We show that the higher rates of protein evolution on rearranged chromosomes observed in the earlier study are not reproduced by our survey of the larger data set. We further show that the conclusion of the earlier study is likely confounded by two factors introduced by the relatively limited sample size: (1) nonuniform distribution of genes in the genome, and (2) stochastic noise in substitution rates inherent to short lineages such as the human-chimpanzee lineage. Our results offer a general cautionary note on the importance of controlling for hidden factors in studies involving bioinformatic surveys.
Animals↗