M. Brent Hawkins

Bio: M. Brent Hawkins is an academic researcher from Harvard University. The author has contributed to research in topics: Adaptation & Evolvability. The author has an hindex of 6, co-authored 9 publications receiving 125 citations. Previous affiliations of M. Brent Hawkins include University of Colorado Boulder & Boston Children's Hospital.

Genetic Screen for Postembryonic Development in the Zebrafish (Danio rerio): Dominant Mutations Affecting Adult Form

Abstract: Large-scale forward genetic screens have been instrumental for identifying genes that regulate development, homeostasis, and regeneration, as well as the mechanisms of disease. The zebrafish, Danio rerio, is an established genetic and developmental model used in genetic screens to uncover genes necessary for early development. However, the regulation of postembryonic development has received less attention as these screens are more labor intensive and require extensive resources. The lack of systematic interrogation of late development leaves large aspects of the genetic regulation of adult form and physiology unresolved. To understand the genetic control of postembryonic development, we performed a dominant screen for phenotypes affecting the adult zebrafish. In our screen, we identified 72 adult viable mutants showing changes in the shape of the skeleton as well as defects in pigmentation. For efficient mapping of these mutants and mutation identification, we devised a new mapping strategy based on identification of mutant-specific haplotypes. Using this method in combination with a candidate gene approach, we were able to identify linked mutations for 22 out of 25 mutants analyzed. Broadly, our mutational analysis suggests that there are key genes and pathways associated with late development. Many of these pathways are shared with humans and are affected in various disease conditions, suggesting constraint in the genetic pathways that can lead to change in adult form. Taken together, these results show that dominant screens are a feasible and productive means to identify mutations that can further our understanding of gene function during postembryonic development and in disease.

Historical contingency shapes adaptive radiation in Antarctic fishes

Abstract: Adaptive radiation illustrates links between ecological opportunity, natural selection and the generation of biodiversity. Central to adaptive radiation is the association between a diversifying lineage and the evolution of phenotypic variation that facilitates the use of new environments or resources. However, is not clear whether adaptive evolution or historical contingency is more important for the origin of key phenotypic traits in adaptive radiation. Here we use targeted sequencing of >250,000 loci across 46 species to examine hypotheses concerning the origin and diversification of key traits in the adaptive radiation of Antarctic notothenioid fishes. Contrary to expectations of adaptive evolution, we show that notothenioids experienced a punctuated burst of genomic diversification and evolved key skeletal modifications before the onset of polar conditions in the Southern Ocean. We show that diversifying selection in pathways associated with human skeletal dysplasias facilitates ecologically important variation in buoyancy among Antarctic notothenioid species, and demonstrate the sufficiency of altered trip11, col1a2 and col1a1a function in zebrafish (Danio rerio) to phenocopy skeletal reduction in Antarctic notothenioids. Rather than adaptation being driven by the cooling of the Antarctic, our results highlight the role of historical contingency in shaping the adaptive radiation of notothenioids. Understanding the historical and environmental context for the origin of key traits in adaptive radiations extends beyond reconstructing events that result in evolutionary innovation, as it also provides a context in forecasting the effects of climate change on the stability and evolvability of natural populations. Phylogenetic comparative analysis of Antarctic notothenioid fishes reveals a burst of genomic diversification and evolution of key skeletal modifications before the onset of polar conditions in the Southern Ocean.

Shared developmental programme strongly constrains beak shape diversity in songbirds

Abstract: The striking diversity of bird beak shapes is an outcome of natural selection, yet the relative importance of the limitations imposed by the process of beak development on generating such variation is unclear. Untangling these factors requires mapping developmental mechanisms over a phylogeny far exceeding model systems studied thus far. We address this issue with a comparative morphometric analysis of beak shape in a diverse group of songbirds. Here we show that the dynamics of the proliferative growth zone must follow restrictive rules to explain the observed variation, with beak diversity constrained to a three parameter family of shapes, parameterized by length, depth and the degree of shear. We experimentally verify these predictions by analysing cell proliferation in the developing embryonic beaks of the zebra finch. Our findings indicate that beak shape variability in many songbirds is strongly constrained by shared properties of the developmental programme controlling the growth zone.

The bowfin genome illuminates the developmental evolution of ray-finned fishes.

Abstract: The bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here we present a chromosome-level genome assembly for bowfin that enables gene-order analyses, settling long-debated neopterygian phylogenetic relationships. We examine chromatin accessibility and gene expression through bowfin development to investigate the evolution of immune, scale, respiratory and fin skeletal systems and identify hundreds of gene-regulatory loci conserved across vertebrates. These resources connect developmental evolution among bony fishes, further highlighting the bowfin's importance for illuminating vertebrate biology and diversity in the genomic era.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

A Systematic Genome-Wide Analysis of Zebrafish Protein-Coding Gene Function

Abstract: Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

The shapes of bird beaks are highly controlled by nondietary factors

Abstract: Bird beaks are textbook examples of ecological adaptation to diet, but their shapes are also controlled by genetic and developmental histories. To test the effects of these factors on the avian craniofacial skeleton, we conducted morphometric analyses on raptors, a polyphyletic group at the base of the landbird radiation. Despite common perception, we find that the beak is not an independently targeted module for selection. Instead, the beak and skull are highly integrated structures strongly regulated by size, with axes of shape change linked to the actions of recently identified regulatory genes. Together, size and integration account for almost 80% of the shape variation seen between different species to the exclusion of morphological dietary adaptation. Instead, birds of prey use size as a mechanism to modify their feeding ecology. The extent to which shape variation is confined to a few major axes may provide an advantage in that it facilitates rapid morphological evolution via changes in body size, but may also make raptors especially vulnerable when selection pressures act against these axes. The phylogenetic position of raptors suggests that this constraint is prevalent in all landbirds and that breaking the developmental correspondence between beak and braincase may be the key novelty in classic passerine adaptive radiations.

Mutations affecting pigmentation and shape of the adult zebrafish

Abstract: Mutations causing a visible phenotype in the adult serve as valuable visible genetic markers in multicellular genetic model organisms such as Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana. In a large scale screen for mutations affecting early development of the zebrafish, we identified a number of mutations that are homozygous viable or semiviable. Here we describe viable mutations which produce visible phenotypes in the adult fish. These predominantly affect the fins and pigmentation, but also the eyes and body length of the adult. A number of dominant mutations caused visible phenotypes in the adult fish. Mutations in three genes, long fin, another long fin and wanda affected fin formation in the adult. Four mutations were found to cause a dominant reduction of the overall body length in the adult. The adult pigment pattern was found to be changed by dominant mutations in wanda, asterix, obelix, leopard, salz and pfeffer. Among the recessive mutations producing visible phenotypes in the homozygous adult, a group of mutations that failed to produce melanin was assayed for tyrosinase activity. Mutations in sandy produced embryos that failed to express tyrosinase activity. These are potentially useful for using tyrosinase as a marker for the generation of transgenic lines of zebrafish.