Article

Forces Shaping the Fastest Evolving Regions in the Human Genome

Department of Biomolecular Engineering , University of California, Santa Cruz, Santa Cruz, California, United States
PLoS Genetics (Impact Factor: 7.53). 11/2006; 2(10):e168. DOI: 10.1371/journal.pgen.0020168
Source: PubMed

ABSTRACT

Synopsis
Studies of differences between the chimpanzee and human genomes have focused on protein-coding genes. However, examples of amino acid changes between chimp and human have not been able to explain most of the phenotypic differences between us and our fellow hominoids. King and Wilson (1975) proposed that the main differences between chimps and humans will be found in non-coding regulatory DNA. Consistent with this hypothesis, recent whole-genome scans for evolutionarily conserved DNA elements that have evolved rapidly since our divergence from the chimp-human ancestor have discovered largely non-coding regions. The authors investigate a carefully screened set of 202 such human accelerated regions (HARs). Most of these HARs do not code for proteins, but instead are located in introns and intergenic regions near protein-coding genes. The set of genes near HARs is enriched for transcription factors, suggesting that the HARs may play important roles in gene regulation. This study also discovers a striking adenine and thymine to guanine and cytosine bias among the human-specific changes in HARs. This suggests the involvement of biased gene conversion or a selective force to increase guanine and cytosine content. Some HARs may also have been under positive selection. Hence, there is likely more than one evolutionary force shaping the fastest evolving regions of the human genome.

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    • "In contrast, it has been estimated that only 55% of HAEs exceed the neutral rate (Kostka et al. 2012). Second, we investigated the contribution of GC-biased gene conversion (GC-BGC) to our data, which influences rate acceleration of HAEs (Pollard et al. 2006a; Galtier and Duret 2007; Duret and Galtier 2009; Kostka et al. 2012), and found that 9.7% (51 haDHSs) show significant evidence of GC-BGC (Supplemental Text; Supplemental Fig. 3a). Finally, we investigated patterns of human–macaque divergence around haDHSs and found that local increases in mutation rate cannot explain rate acceleration in haDHSs, although mutation rate heterogeneity has influenced previous inferences of HAEs (Supplemental Text; Supplemental Fig. 3b; Pollard et al. 2006b; Prabhakar et al. 2006; Bush and Lahn 2008; Lindblad- Toh et al. 2011). "
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    ABSTRACT: It has long been hypothesized that changes in gene regulation have played an important role in human evolution, but regulatory DNA has been much more difficult to study compared with protein-coding regions. Recent large-scale studies have created genome-scale catalogs of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To better define regulatory DNA that has been subject to human-specific adaptive evolution, we performed comprehensive evolutionary and population genetics analyses on over 18 million DHSs discovered in 130 cell types. We identified 524 DHSs that are conserved in nonhuman primates but accelerated in the human lineage (haDHS), and estimate that 70% of substitutions in haDHSs are attributable to positive selection. Through extensive computational and experimental analyses, we demonstrate that haDHSs are often active in brain or neuronal cell types; play an important role in regulating the expression of developmentally important genes, including many transcription factors such as SOX6, POU3F2, and HOX genes; and identify striking examples of adaptive regulatory evolution that may have contributed to human-specific phenotypes. More generally, our results reveal new insights into conserved and adaptive regulatory DNA in humans and refine the set of genomic substrates that distinguish humans from their closest living primate relatives.
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    • "013 , for review ) . Three non - coding intronic regions of interest in evolutionary terms have been found within AUTS2 : the human accelerated region HAR31 , located in intron 4 ( Prabhakar et al . , 2006 ) , and the human accelerated conserved non - coding sequences ( haCNSs ) HACNS 369 and HACNS 174 , located in introns 1 and 4 , respectively ( Pollard et al . , 2006 ) . Interestingly , these regions contain enhancers that seem to be active in the brain . Within the region under selective sweep Oksenberg et al . ( 2013 ) found six enhancers that show expression in the brain and four mouse enhancers that are active in the midbrain and the eye . Some of these enhancers are also found inside the HAR or"

    No preview · Article · Aug 2015 · Frontiers in Cellular Neuroscience
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    • "013 , for review ) . Three non - coding intronic regions of interest in evolutionary terms have been found within AUTS2 : the human accelerated region HAR31 , located in intron 4 ( Prabhakar et al . , 2006 ) , and the human accelerated conserved non - coding sequences ( haCNSs ) HACNS 369 and HACNS 174 , located in introns 1 and 4 , respectively ( Pollard et al . , 2006 ) . Interestingly , these regions contain enhancers that seem to be active in the brain . Within the region under selective sweep Oksenberg et al . ( 2013 ) found six enhancers that show expression in the brain and four mouse enhancers that are active in the midbrain and the eye . Some of these enhancers are also found inside the HAR or"
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    ABSTRACT: The sequencing of the genomes from extinct hominins has revealed that changes in some brain-related genes have been selected after the split between anatomically-modern humans and Neanderthals/Denisovans. To date, no coherent view of these changes has been provided. Following a line of research we initiated in Boeckx and Benítez-Burraco (2014a), we hypothesize functional links among most of these genes and their products, based on the existing literature for each of the gene discussed. The genes we focus on are found mutated in different cognitive disorders affecting modern populations and their products are involved in skull and brain morphology, and neural connectivity. If our hypothesis turns out to be on the right track, it means that the changes affecting most of these proteins resulted in a more globular brain and ultimately brought about modern cognition, with its characteristic generativity and capacity to form and exploit cross-modular concepts, properties most clearly manifested in language.
    Full-text · Article · Jun 2015 · Frontiers in Psychology
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