Convergent and lineage-specific genomic differences in limb regulatory elements in limbless reptile lineages

Roscito, Juliana G.; Sameith, Katrin; Kirilenko, Bogdan; Hecker, Nikolai; Winkler, Sylke; Dahl, Andreas; Rodrigues, Miguel Tréfaut; Hiller, Michael

doi:10.1016/j.celrep.2021.110280

Cited by 29 publications

(22 citation statements)

References 134 publications

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“…In conclusion, the limited evidence for use of altered Pitx1 expression in hindlimb reduced squamates may result from the absence of the hindlimb‐specific enhancer, PelA , small effects of PelB , or the adverse pleiotropic effects of a disrupted Pen enhancer. Our findings are consistent with available evidence from non‐model organisms that there are multiple developmental and molecular routes to hindlimb reduction (Roscito et al, 2022; Swank et al, 2021). Consequently, hindlimb loss is likely non‐parallel in squamates and Pitx1 is only one of the several genetic pathways that could be used to respond to similar selection pressures.…”

Section: Discussionsupporting

confidence: 92%

“…Nevertheless, a recent review of molecular and developmental evidence from multiple clades of non‐model vertebrates with hind appendage reduction found that Pitx1 use appears to be limited to sticklebacks and manatees (Swank et al, 2021). Moreover, a recent comparative genomics study of three limb‐reduced reptile lineages found that the molecular basis of limb loss was not convergent and in no lineage was Pitx1 a major driver (Roscito et al, 2022). In this study, we corroborate the findings of Swank et al (2021) and Roscito et al (2022) with new data collected from six lizard clades that independently evolved hindlimb reduction.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, a recent comparative genomics study of three limb‐reduced reptile lineages found that the molecular basis of limb loss was not convergent and in no lineage was Pitx1 a major driver (Roscito et al, 2022). In this study, we corroborate the findings of Swank et al (2021) and Roscito et al (2022) with new data collected from six lizard clades that independently evolved hindlimb reduction. We tested for Pitx1 ’s signature of left‐larger asymmetry in vestigial hindlimbs and found left‐larger asymmetry in only one species.…”

Section: Introductionmentioning

confidence: 99%

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Attempting genetic inference from directional asymmetry during convergent hindlimb reduction in squamates

Swank

Elazegui

Janidlo

et al. 2022

Ecology and Evolution

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Loss and reduction in paired appendages are common in vertebrate evolution. How often does such convergent evolution depend on similar developmental and genetic pathways? For example, many populations of the threespine stickleback and ninespine stickleback (Gasterosteidae) have independently evolved pelvic reduction, usually based on independent mutations that caused reduced Pitx1 expression. Reduced Pitx1 expression has also been implicated in pelvic reduction in manatees. Thus, hindlimb reduction stemming from reduced Pitx1 expression has arisen independently in groups that diverged tens to hundreds of millions of years ago, suggesting a potential for repeated use of Pitx1 across vertebrates. Notably, hindlimb reduction based on the reduction in Pitx1 expression produces left-larger directional asymmetry in the vestiges. We used this phenotypic signature as a genetic proxy, testing for hindlimb directional asymmetry in six genera of squamate reptiles that independently evolved hindlimb reduction and for which genetic and developmental tools are not yet developed: Agamodon anguliceps, Bachia intermedia, Chalcides sepsoides, Indotyphlops braminus, Ophisaurus attenuatuas and O. ventralis, and Teius teyou. Significant asymmetry occurred in one taxon, Chalcides sepsoides, whose left-side pelvis and femur vestiges were 18% and 64% larger than right-side vestiges, respectively, suggesting modification in Pitx1 expression in that species. However, there was either right-larger asymmetry or no directional asymmetry in the other five taxa, suggesting multiple developmental genetic pathways to hindlimb reduction in squamates and the vertebrates more generally.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Attempting genetic inference from directional asymmetry during convergent hindlimb reduction in squamates

Swank

Elazegui

Janidlo

et al. 2022

Ecology and Evolution

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“…In addition to this, comparative genomic and evolutionary developmental biology approaches have examined genetic variation or gene expression between related species with differing phenotypes to pinpoint genes associated with the skeletal form. This line of work has produced several insights into the genetic basis of skeletal structure from the underpinnings of convergent limb loss in snakes and limbless lizards ( 14, 15 ) to increased limb lengths in jerboas when compared to mice ( 16 ). Analyses studying differences in gene expression and regulation in skeletal tissues between humans and other primates have recently identified a gene involved in tail loss in great apes ( 17 ), as well as shown that open chromatin regions specific to the human knee and hip joint overlap with regions that are evolutionarily accelerated in humans ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

The genetic architecture of the human skeletal form

Kun

Javan

Smith

et al. 2023

Preprint

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The human skeletal form underlies our ability to walk on two legs, but unlike standing height, the genetic basis of limb lengths and skeletal proportions is less well understood. Here we applied a deep learning model to 31,221 whole body dual-energy X-ray absorptiometry (DXA) images from the UK Biobank (UKB) to extract 23 different image-derived phenotypes (IDPs) that include all long bone lengths as well as hip and shoulder width, which we analyzed while controlling for height. All skeletal proportions are highly heritable (~40-50%), and genome-wide association studies (GWAS) of these traits identified 179 independent loci, of which 102 loci were not associated with height. These loci are enriched in genes regulating skeletal development as well as associated with rare human skeletal diseases and abnormal mouse skeletal phenotypes. Genetic correlation and genomic structural equation modeling indicated that limb proportions exhibited strong genetic sharing but were genetically independent of width and torso proportions. Phenotypic and polygenic risk score analyses identified specific associations between osteoarthritis (OA) of the hip and knee, the leading causes of adult disability in the United States, and skeletal proportions of the corresponding regions. We also found genomic evidence of evolutionary change in arm-to-leg and hip-width proportions in humans consistent with striking anatomical changes in these skeletal proportions in the hominin fossil record. In contrast to cardiovascular, auto-immune, metabolic, and other categories of traits, loci associated with these skeletal proportions are significantly enriched in human accelerated regions (HARs), and regulatory elements of genes differentially expressed through development between humans and the great apes. Taken together, our work validates the use of deep learning models on DXA images to identify novel and specific genetic variants affecting the human skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.

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“…However, the conserved ZRS element is absent in the three caecilian species. In contrast, ZRS is intact in limbless lizards where a more complex and lineage-specific route to limblessness has been proposed 33 . Here, the absence of ZRS in caecilians, and the functional work on the mutated form of ZRS in snakes, provides us with a common molecular target for the convergent loss of limbs in snakes and caecilians.…”

mentioning

confidence: 99%

Caecilian genomes reveal the molecular basis of adaptation, and convergent evolution of limblessness in snakes and caecilians

Ovchinnikov

Uliano-Silva

Wilkinson

et al. 2022

Preprint

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We present genome sequences for Geotrypetes seraphini (3.8Gb) and Microcaecilia unicolor (4.7Gb) caecilians, a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. We identify signatures of positive selection unique to caecilians in 1,150 orthogroups, with enrichment of functions for olfaction and detection of chemical signals. All our caecilian genomes are missing the ZRS enhancer of Sonic Hedgehog, shown by in vivo deletions to be required for limb development in mice and also absent in snakes, thus revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.

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Convergent and lineage-specific genomic differences in limb regulatory elements in limbless reptile lineages

Cited by 29 publications

References 134 publications

Attempting genetic inference from directional asymmetry during convergent hindlimb reduction in squamates

Attempting genetic inference from directional asymmetry during convergent hindlimb reduction in squamates

The genetic architecture of the human skeletal form

Caecilian genomes reveal the molecular basis of adaptation, and convergent evolution of limblessness in snakes and caecilians

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