Detecting Selection in Noncoding Regions of Nucleotide Sequences

Wong, Wendy S. W.; Nielsen, Rasmus

doi:10.1534/genetics.102.010959

Cited by 120 publications

(123 citation statements)

References 40 publications

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“…The prolactin promoter region (chr6: 22,303,070-22,303,383 on human GRCh37 assembly) was tested for evidence of positive selection using likelihood-based models implemented in an updated version of the software EvoNC (35) Fig. 6.…”

Section: Methodsmentioning

confidence: 99%

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

Emera

Wagner

2012

Proc. Natl. Acad. Sci. U.S.A.

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Transposable elements (TEs) are known to provide DNA for host regulatory functions, but the mechanisms underlying the transformation of TEs into cis-regulatory elements are unclear. In humans two TEs-MER20 and MER39-contribute the enhancer/ promoter for decidual prolactin (dPRL), which is dramatically induced during pregnancy. We show that evolution of the strong human dPRL promoter was a multistep process that took millions of years. First, MER39 inserted near MER20 in the primate/rodent ancestor, and then there were two phases of activity enhancement in primates. Through the mapping of causal nucleotide substitutions, we demonstrate that strong promoter activity in apes involves epistasis between transcription factor binding sites (TFBSs) ancestral to MER39 and derived sites. We propose a mode of molecular evolution that describes the process by which MER20/MER39 was transformed into a strong promoter, called "epistatic capture." Epistatic capture is the stabilization of a TFBS that is ancestral but variable in outgroup lineages, and is fixed in the ingroup because of epistatic interactions with derived TFBSs. Finally, we note that evolution of human promoter activity coincides with the emergence of a unique reproductive character in apes, highly invasive placentation. Because prolactin communicates with immune cells during pregnancy, which regulate fetal invasion into maternal tissues, we speculate that ape dPRL promoter activity evolved in response to increased invasiveness of ape fetal tissue.cis-regulatory evolution | human evolution | human pregnancy I n the pursuit to understand mechanisms underlying the evolution of gene regulation, it has become increasingly clear that transposable elements play a critical role in regulatory evolution by providing novel genetic elements, including new introns, promoters, enhancers, and insulators (1). In addition to individual examples showing that transposable elements (TEs) are associated with host regulatory function, computational work shows that TEs intersect with many promoter regions (2) and are overrepresented in predicted regulatory regions [(3, 4); see review by Feschotte (1)]. Many questions remain unanswered. How frequently are TEs actually co-opted for regulatory function? What is the adaptive significance of these events? Are TEs used by the host genome immediately upon insertion or do they require extensive sequence evolution before acquiring a biological role? What are the molecular changes that transform a transposable element into a cisregulatory element?In this paper we address the latter two questions posed above by investigating evolution of the decidual prolactin promoter in primates. In a recent paper we showed that the prolactin gene was independently recruited into uterine expression in primates, mice, and elephants by the co-option of different transposable elements, highlighting the frequency at which TEs can be recruited and their importance in gene regulatory innovation (5). Here we trace the evolutionary history and function of transposabl...

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Section: Methodsmentioning

confidence: 99%

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

Emera

Wagner

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Ref. 25). For each model, we took the best of 10 fits starting from random points, thus guarding against local maxima of the likelihood function.…”

Section: Mmp20 Hsd17b4 Ushbp1mentioning

confidence: 99%

“…1b). The fitted parameters include ζ (zeta), the ratio of substitution rates in the promoter region to those in the associated intronic sequences 25 ; ζ is analogous to the ratio of substitution rates at nonsynonymous sites to those at synonymous sites in coding sequences. The null model constrains ζ to be less than or equal 1, representing negative or no selection on the promoter region, whereas the alternate model allows ζ to be greater than 1 on the human lineage, representing positive selection on the promoter region.…”

mentioning

confidence: 99%

Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution

et al. 2007

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Surveys of protein-coding sequences for signatures of positive selection in humans and chimpanzees have flagged surprisingly few genes known to be involved in neural or nutritional processes 1-5 , despite the pronounced differences between humans and chimpanzees in behavior, cognition, and diet 6-8 . It may be that most such differences are due to changes in gene regulation rather than protein structure 9 . Here, we present the first survey of promoter (5 -flanking) regions, which are rich in cis-regulatory sequences, for signatures of positive selection on the human lineage. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly glucose metabolism.Cognitive, behavioral, and dietary differences are among the most conspicuous differences between humans and their closest relatives, chimpanzees and other great apes. For example, even in the absence of written language or agriculture, human communication and tools are much more complex than those of chimpanzees 6,7 , and humans consume a far wider range of foods than chimpanzees 8 . These traits are essential to many aspects of human ecology, such as the broad range of habitats humans occupy 8 , and although assessing the adaptive significance of a trait is often challenging, it is plausible that many human cognitive, behavioral, and dietary traits are adaptations. Consistent with this, the protein-coding sequences of several genes known to function in neural or nutritional processes have been shown to bear signatures of positive selection (natural or sexual selection for novel alleles) in humans 10,11 . Surprisingly, however, such genes are not prominent in surveys of coding sequences for evidence of positive selection in humans and chimpanzees [1][2][3][4][5] . Instead, these surveys have flagged many genes known to function in immunity, olfaction, and spermatogenesis, among other processes. Neural-related genes in particular show little sign of positive selection in these surveys 3, 4 .One possible explanation, first suggested by King and Wilson 9 , is that many phenotypic differences between humans and chimpanzees may be due to changes in gene regulation rather than protein structure. In particular, the genetic bases of human neural and nutritional adaptations may reside primarily in cis-regulatory sequences (DNA where proteins bind sequence-specifically to regulate transcription), very few of which lie within coding sequences 12 . Several recent studies point in this direction. First, of the two most thoroughly investigated cases of positive selection on cis-regulatory sequences in humans, one, PDYN, is neural-related 13 , and the other, LCT, is nutrition-related 14 . Second, two surveys of linkage disequilibrium among single-nucleotide polymorphisms for signatures of very recent positive selection within human populations, embracing both coding and noncoding sequences, found excesses of s...

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“…Another is Fay and Wu's H statistic, which was employed by Rockman et al to detect positive selection in the regulatory region of PDYN, an endogenous opiate receptor ligand [13]. One molecular evolutionary test that uses non-coding sequence is the approach proposed by Wong and Nielsen to detect positive selection in the non-coding regions of a gene using both its coding and non-coding sequence [14]. The motivating idea behind these and many other studies is that departures from the neutral model of molecular evolution are likely to indicate natural selection.…”

Section: Introductionmentioning

confidence: 99%

Forces Shaping the Fastest Evolving Regions in the Human Genome

Pollard¹,

Salama²,

King³

et al. 2005

PLoS Genet

137

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Comparative genomics allow us to search the human genome for segments that were extensively changed in the last ;5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements are dramatically changed in human but not in other primates, with seven times more substitutions in human than in chimp. The accelerated elements, and in particular the top five, show a strong bias for adenine and thymine to guanine and cytosine nucleotide changes and are disproportionately located in high recombination and high guanine and cytosine content environments near telomeres, suggesting either biased gene conversion or isochore selection. In addition, there is some evidence of directional selection in the regions containing the two most accelerated regions. A combination of evolutionary forces has contributed to accelerated evolution of the fastest evolving elements in the human genome.

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Detecting Selection in Noncoding Regions of Nucleotide Sequences

Cited by 120 publications

References 40 publications

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution

Forces Shaping the Fastest Evolving Regions in the Human Genome

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