A Comparative Study of the Evolution of Mammalian High-Frequency Hearing and Echolocation

PhDThe lineage that gave rise to mammals split from other basal amniotes, approximately 300 million years ago. Since then, mammals have evolved many sensory novelties, including high-frequency hearing and echolocation. Sensitivity to high frequencies is particularly well developed in many echolocating mammals; for example, the upper hearing limit of several laryngeal echolocating bat species are estimated to be approximately ten times that of humans. In order to process the high frequency sounds produced during echolocation, the inner ears of laryngeal echolocating bats have undergone substantial modifications. Despite the evolutionary significance of laryngeal echolocation, it is unknown how many times it evolved within bats. Its occurrence on most, but not all, bat lineages suggests it either evolved once with secondary loss, or independently on multiple lineages. Distinguishing between these possibilities is complicated by morphological diversity and convergence. Furthermore, the genetic basis underpinning echolocation remains largely unknown. To elucidate the evolutionary history of this key trait in bats, a combined molecular and morphological approach was taken. Firstly, for two mammalian ‘hearing genes’ sequence convergence, phylogenetic signal and selection pressures were examined across echolocating and non-echolocating mammal species. Secondly, substitution rates of Conserved Non-coding Elements associated with genes regulating ear development were compared across mammals. Finally, as mammalian inner ear development is controlled by many genes, the gross structure of the bony labyrinth was studied in order to examine the combined genetic effect. Structural variation of bat cochleae and vestibular systems was examined using micro-computed tomography reconstructions, and related to ecological data. Subsequent analyses found evidence of convergence at the molecular level, in terms of amino acid substitutions, and also the morphological level, in terms of inner ear morphology. No evidence of degeneration, supporting loss-of-function in Old World fruit bats was found. Conversely, evidence of differential evolution pressures acting on the two echolocating bat lineages was found, which supports multiple origins of laryngeal echolocation in bats.NERC; CRF; CEE; SRF; Teeling lab

Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan—a key constituent of the extracellular matrix—that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African mole-rat clade.National Research Foundation (South Africa

A phylomedicine approach to understanding the evolution of auditory sensory perception and disease in mammals

Hereditary deafness affects 0.1% of individuals globally and is considered as one of the most debilitating diseases of man. Despite recent advances, the molecular basis of normal auditory function is not fully understood and little is known about the contribution of single-nucleotide variations to the disease. Using cross-species comparisons of 11 'deafness' genes (Myo15, Ush1g, Strc, Tecta, Tectb, Otog, Col11a2, Gjb2, Cldn14, Kcnq4, Pou3f4) across 69 evolutionary and ecologically divergent mammals, we elucidated whether there was evidence for: (i) adaptive evolution acting on these genes across mammals with similar hearing capabilities; and, (ii) regions of long-term evolutionary conservation within which we predict disease-associated mutations should occur. We find evidence of adaptive evolution acting on the eutherian mammals in Myo15, Otog and Tecta. Examination of selection pressures in Tecta and Pou3f4 across a taxonomic sample that included a wide representation of auditory specialists, the bats, did not uncover any evidence for a role in echolocation. We generated ‘conservation indices' based on selection estimates at nucleotide sites and found that known disease mutations fall within sites of high evolutionary conservation. We suggest that methods such as this, derived from estimates of evolutionary conservation using phylogenetically divergent taxa, will help to differentiate between deleterious and benign mutations

Molecular evolution of the hyaluronan synthase 2 gene in mammals : implications for adaptations to the subterranean niche and cancer resistance

The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan—a key constituent of the extracellular matrix—that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African molerat clade.DST-NRF SARChI Chair for Behavioural Ecology and Physiology.European Research Council.http://rsbl.royalsocietypublishing2016-05-31hb201

Family wide molecular adaptations to underground life in African mole-rats revealed by phylogenomic analysis

During their evolutionary radiation, mammals have colonized diverse habitats. Arguably the subterranean niche is the most inhospitable of these, characterized by reduced oxygen, elevated carbon dioxide, absence of light, scarcity of food, and a substrate that is energetically costly to burrow through. Of all lineages to have transitioned to a subterranean niche, African mole-rats are one of the most successful. Much of their ecological success can be attributed to a diet of plant storage organs, which has allowed them to colonize climatically varied habitats across sub-Saharan Africa, and has probably contributed to the evolution of their diverse social systems. Yet despite their many remarkable phenotypic specializations, little is known about molecular adaptations underlying these traits. To address this, we sequenced the transcriptomes of seven mole-rat taxa, including three solitary species, and combined new sequences with existing genomic data sets. Alignments of more than 13,000 protein-coding genes encompassed, for the first time, all six genera and the full spectrum of ecological and social variation in the clade. We detected positive selection within the mole-rat clade and along ancestral branches in approximately 700 genes including loci associated with tumorigenesis, aging, morphological development, and sociality. By combining these results with gene ontology annotation and protein–protein networks, we identified several clusters of functionally related genes. This family wide analysis of molecular evolution in mole-rats has identified a suite of positively selected genes, deepening our understanding of the extreme phenotypic traits exhibited by this group.The European Research Council (ERC Starting grant 310482 [EVOGENO]) awarded to S.J.R.; the DST-NRF SARChI Chair of Mammalian Behavioral Ecology and Physiology (grant number 64756) (funds to N.C.B.).http://mbe.oxfordjournals.orghb201

Molecular evolution of growth hormone and insulin-like growth factor 1 receptors in long-lived, small-bodied mammals

Mammals typically display a robust positive relationship between lifespan and body size. Two groups that deviate markedly from this pattern are bats and African mole-rats, with members of both groups being extremely long-lived given their body size, with the maximum documented lifespan for many species exceeding 20 years. A recent genomics study of the exceptionally long-lived Brandt's bat, Myotis brandtii (41 years), suggested that its longevity and small body size may be at least partly attributed to key amino acid substitutions in the transmembrane domains of the receptors of growth hormone (GH) and insulin-like growth factor 1 (IGF1). However, whereas elevated longevity is likely to be common across all 19 bat families, the reported amino acid substitutionswere only observed in two closely related bat families. To test the hypothesis that an altered GH/IGF1 axis relates to the longevity of African mole-rats and bats,we compared and analysed the homologous coding gene sequences in genomic and transcriptomic data from 26 bat species, five mole-rats and 38 outgroup species. Phylogenetic analyses of both genes recovered themajority of nodes in the currently accepted species tree with high support. Compared to other clades, such as primates and carnivores, the bats and rodents had longer branch lengths. The single 24 amino acid transmembrane domain of IGF1Rwas found to bemore conserved across mammals compared to that of GHR.Within bats, considerable variation in the transmembrane domain of GHR was found, including a previously unreported deletion in Emballonuridae. The transmembrane domains of rodents were found to be more conserved, with mole-rats lacking uniquely conserved amino acid substitutions. Molecular evolutionary analyses showed that both genes were under purifying selection in bats andmole-rats. Our findings suggest thatwhile the previously documentedmutations may confer some additional lifespan to Myotis bats, other, as yet unknown, genetic differences are likely to account for the long lifespans observed in many bat and mole-rat species.DST–NRF SARChI Chair for Behavioural Ecology and Physiology (64756), the European Research Council (310482 EVOGENO) and the National Science Foundation (DEB-0949759).http//www.elsevier.com/locate/genehb201

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Large-scale genome sampling reveals unique immunity and metabolic adaptations in bats

SCV was supported by a Max Planck Research Group awarded by the Max Planck Gesellschaft, a Human Frontiers Science Program Grant (RGP0058/2016) and a UKRI Future Leaders Fellowship (MR/T021985/1).Comprising more than 1,400 species, bats possess adaptations unique among mammals including powered flight, unexpected longevity, and extraordinary immunity. Some of the molecular mechanisms underlying these unique adaptations includes DNA repair, metabolism and immunity. However, analyses have been limited to a few divergent lineages, reducing the scope of inferences on gene family evolution across the Order Chiroptera. We conducted an exhaustive comparative genomic study of 37 bat species, one generated in this study, encompassing a large number of lineages, with a particular emphasis on multi-gene family evolution across immune and metabolic genes. In agreement with previous analyses, we found lineage-specific expansions of the APOBEC3 and MHC-I gene families, and loss of the proinflammatory PYHIN gene family. We inferred more than 1,000 gene losses unique to bats, including genes involved in the regulation of inflammasome pathways such as epithelial defence receptors, the natural killer gene complex and the interferon-gamma induced pathway. Gene set enrichment analyses revealed genes lost in bats are involved in defence response against pathogen-associated molecular patterns and damage-associated molecular patterns. Gene family evolution and selection analyses indicate bats have evolved fundamental functional differences compared to other mammals in both innate and adaptive immune system, with the potential to enhance antiviral immune response while dampening inflammatory signalling. In addition, metabolic genes have experienced repeated expansions related to convergent shifts to plant-based diets. Our analyses support the hypothesis that, in tandem with flight, ancestral bats had evolved a unique set of immune adaptations whose functional implications remain to be explored.PostprintPeer reviewe

Trends in International Cancer Research Investment 2006-2018.

The International Cancer Research Partnership (ICRP) is an active network of cancer research funding organizations, sharing information about funded research projects in a common database. Data are publicly available to enable the cancer research community to find potential collaborators and avoid duplication. This study presents an aggregated analysis of projects funded by 120 partner organizations and institutes in 2006-2018, to highlight trends in cancer research funding. Overall, the partners' funding for cancer research increased from $5.562 billion (bn) US dollars (USD) in 2006 to$8.511bn USD in 2018, an above-inflation increase in funding. Analysis by the main research focus of projects using Common Scientific Outline categories showed that Treatment was the largest investment category in 2018, followed by Early Detection, Diagnosis, and Prognosis; Cancer Biology; Etiology; Control, Survivorship, and Outcomes; and Prevention. Over the 13 years covered by this analysis, research funding into Treatment and Early Detection, Diagnosis, and Prognosis had increased in terms of absolute investment and as a proportion of the portfolio. Research funding in Cancer Biology and Etiology declined as a percentage of the portfolio, and funding for Prevention and Control, Survivorship and Outcomes remained static. In terms of cancer site-specific research, funding for breast cancer and colorectal cancer had increased in absolute terms but declined as a percentage of the portfolio. By contrast, investment for brain cancer, lung cancer, leukemia, melanoma, and pancreatic cancer increased both in absolute terms and as a percentage of the portfolio