Article

Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, 98195, USA.
Cell (Impact Factor: 31.96). 05/2012; 149(4):912-22. DOI: 10.1016/j.cell.2012.03.033
Source: PubMed

ABSTRACT Gene duplication is an important source of phenotypic change and adaptive evolution. We leverage a haploid hydatidiform mole to identify highly identical sequences missing from the reference genome, confirming that the cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) duplicated three times exclusively in humans. We show that the promoter and first nine exons of SRGAP2 duplicated from 1q32.1 (SRGAP2A) to 1q21.1 (SRGAP2B) ∼3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (SRGAP2D) ∼2.4 and ∼1 mya, respectively. Sequence and expression analyses show that SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Our data suggest a mechanism where incomplete duplication created a novel gene function-antagonizing parental SRGAP2 function-immediately "at birth" 2-3 mya, which is a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.

0 Bookmarks
 · 
109 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Slit repulsion, mediated by Robo receptors, is known to play a major role in axon guidance in the nervous system. However, recent studies have revealed that in the mammalian cortex these molecules are highly versatile and that their function extends far beyond axon guidance. They act at all phases of development to control neurogenesis, neuronal migration, axon patterning, dendritic outgrowth and spinogenesis. The expression of Robo receptors in cortical and thalamocortical axons (TCAs) is tightly regulated by a combination of transcription factors (TFs), proteases and activity. These findings also suggest that Slit and Robos have influenced the evolution of cortical circuits. Last, novel genetic evidence associates various neurological disorders, such as autism, to abnormal Slit/Robo signaling.
    Current opinion in neurobiology 03/2014; 27C:82-88. · 7.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genomic information allows population relatedness to be inferred and selected genes to be identified. Single nucleotide polymorphism microarray (SNP-chip) data, a proxy for genome composition, contains patterns in allele order and proportion. These patterns can be quantified by compression efficiency (CE). In principle, the composition of an entire genome can be represented by a CE number quantifying allele representation and order. We applied a compression algorithm (DEFLATE) to genome-wide high-density SNP data from 4,155 human, 1,800 cattle, 1,222 sheep, 81 dogs and 49 mice samples. All human ethnic groups can be clustered by CE and the clusters recover phylogeography based on traditional fixation index (FST) analyses. CE analysis of other mammals results in segregation by breed or species, and is sensitive to admixture and past effective population size. This clustering is a consequence of individual patterns such as runs of homozygosity. Intriguingly, a related approach can also be used to identify genomic loci that show population-specific CE segregation. A high resolution CE 'sliding window' scan across the human genome, organised at the population level, revealed genes known to be under evolutionary pressure. These include SLC24A5 (European and Gujarati Indian skin pigmentation), HERC2 (European eye color), LCT (European and Maasai milk digestion) and EDAR (Asian hair thickness). We also identified a set of previously unidentified loci with high population-specific CE scores including the chromatin remodeler SCMH1 in Africans and EDA2R in Asians. Closer inspection reveals that these prioritised genomic regions do not correspond to simple runs of homozygosity but rather compositionally complex regions that are shared by many individuals of a given population. Unlike FST, CE analyses do not require ab initio population comparisons and are amenable to the hemizygous X chromosome. We conclude with a discussion of the implications of CE for a complex systems science view of genome evolution. CE allows one to clearly visualise the evolution of individual genomes and populations through a formal, mathematically-rigorous information space. Overall, CE makes a set of biological predictions, some of which are unique and await functional validation.
    BMC Bioinformatics 03/2014; 15(1):66. · 3.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Research into when and where modern humans originated and how they differ from, and interacted with, other now-extinct forms of human has so far been the realm of archaeologists and paleoanthropologists. However, over the past decade, molecular geneticists have begun to study genomes of extinct humans. Here, I discuss where we stand today with respect to understanding how modern humans came to differ from Neandertals and other human forms that existed until about 30,000 years ago.
    Cell 03/2014; 157(1):216-226. · 31.96 Impact Factor

Full-text

View
1 Download
Available from