Evolving New Skeletal Traits by cis -Regulatory Changes in Bone Morphogenetic Proteins

Abstract

SUMMARY Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone size differences in sticklebacks maps to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form.

Coupled enhancer and coding sequence evolution of a homeobox gene shaped leaf diversity

“…These findings highlight the importance of coordinated coding and regulatory sequence evolution for morphological variation. They also indicate that coupling protein and cis-regulatory evolution (Prud'homme et al 2006;Stern and Orgogozo 2008;Chan et al 2010;Frankel et al 2011;Indjeian et al 2016) can effectively minimize the pleiotropic effects of mutations in developmental genes. Notably, regulatory sequence variation in humans may minimize the detrimental effects of deleterious coding sequence mutations in highly expressed haplotypes (Lappalainen et al 2011).…”

“…Understanding the genetic basis for evolutionary change is a fundamental problem in biology. Morphological diversity is often underpinned by cis-regulatory divergence of developmental genes and consequent spatiotemporal modification of their expression (Gompel et al 2005;Hay and Tsiantis 2006;Prud'homme et al 2006;Carroll 2008;Chan et al 2010;Frankel et al 2011;Studer et al 2011;Arnoult et al 2013;Rast-Somssich et al 2015;Indjeian et al 2016). However, the origin of specific cisregulatory elements underlying morphological diversity is still poorly understood (Rebeiz et al 2015).…”

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

“…In addition, a combination of QTL mapping and genome scan has identified a freshwater-specific allele at the growth/differentiation factor 6 (GDF6) locus, which results in a gain of expression of that gene in the developing epithelium and, ultimately, in a reduction of lateral plate size (Indjeian et al 2016). Like for KITLG, this case also opened a window into human evolution as it was found that a GDF6 hindlimb-specific enhancer was lost in the human lineage, with skeletal modifications obtained in mice that suggest a potential role in the evolution of bipedalism (Indjeian et al 2016).…”

Toward conservation of genetic and phenotypic diversity in Japanese sticklebacks

“…In several cases, genes or even genetic changes that cause morphological divergence have been identified (Colosimo et al, 2005;Miller et al, 2007;Chan et al, 2010;Cleves et al, 2014;O'Brown et al, 2015;Indjeian et al, 2016). cis-Regulatory changes in key developmental genes, such as Eda, Pitx1 and GDF6, contribute to morphological divergence between populations inhabiting contrasting environments (Chan et al, 2010;O'Brown et al, 2015;Indjeian et al, 2016). Furthermore, recent advances in genomic technologies make it possible to find regions under divergent selection between populations in multiple pairs of ecotypes (Mäkinen et al, 2008a(Mäkinen et al, , 2008bHohenlohe et al, 2010;Jones et al, 2012aJones et al, , 2012bRoesti et al, 2014Roesti et al, , 2015Feulner et al, 2015).…”

“…During the last two decades, the genetic architectures of phenotypic divergence between populations have been extensively studied (Peichel et al, 2001;Colosimo et al, 2004;Cresko et al, 2004;Albert et al, 2008;Kitano et al, 2009;Shapiro et al, 2009;Greenwood et al, 2011Greenwood et al, , 2013Wark et al, 2012;Laine et al, 2013Laine et al, , 2014Arnegard et al, 2014;Miller et al, 2014). In several cases, genes or even genetic changes that cause morphological divergence have been identified (Colosimo et al, 2005;Miller et al, 2007;Chan et al, 2010;Cleves et al, 2014;O'Brown et al, 2015;Indjeian et al, 2016). cis-Regulatory changes in key developmental genes, such as Eda, Pitx1 and GDF6, contribute to morphological divergence between populations inhabiting contrasting environments (Chan et al, 2010;O'Brown et al, 2015;Indjeian et al, 2016).…”