Biology subjects

Lowe, C. B.

Publications and source records attributed to Lowe, C. B..

9 recordsLinked to original sources

bioRxiv2025

Rapid and repeated evolution of myosin copy number in threespine stickleback

Copy number variants at genomic loci evolve at a high rate, are linked to many different diseases, and play a role in adaptive evolution in humans and other organisms. Here we show that stickleback fish from freshwater environments have rapidly and repeatedly evolved an expanded number of copies of a gene family involved in muscle development, Myosin Heavy Chain 3 Cluster C (MYH3C), compared to marine populations. Differences in copy number between marine and freshwater fish are maintained even in the presence of gene flow, suggesting that MYH3C changes represent adaptive divergence between ecotypes. Copy number expansion occurs by tandem duplication of MYH3C coding and regulatory regions on the stickleback sex chromosome. We identify a muscle regulatory enhancer within the expanded MYH3C region and show that elevated copy number is associated with developmental and tissue-specific increases in corresponding mRNA expression levels in skeletal muscle. Common MYH3C clusters include 3-, 4-, 5-, and 6-copy variants that likely evolved through a combination of microhomology-mediated break repair and non-allelic homologous recombination. Our results provide a new example of copy number changes in a wild species and identify CNVs as potential "hotspots" of repeated adaptive evolution.

evolutionary biology↗

bioRxiv2025

Segmentally duplicated regulatory elements undergo human-specific rewiring

Gene regulatory innovation underlies many phenotypic transitions. Transposable elements are an established mechanism for creating families of cis-acting elements with shared sequence features and the potential to establish co-regulatory networks. To understand additional mechanisms by which co-regulatory networks form, we define families of noncoding elements based on sequence similarity and cell type-specific activity. We apply this analysis framework to the human telomere-to-telomere genome assembly and embryonic stem cell chromatin accessibility data. We identify segmental duplications as the major mechanism establishing these families, creating over one thousand networks of elements with open chromatin in embryonic stem cells. We functionally validate a subset of these networks as families of regulatory elements with STARR-seq and identify their target genes with CRISPRi in embryonic stem cells. Following segmental duplication, we find that regulatory elements at times maintain their relationship to target genes, and at times rewire to form novel connections. During this rewiring, we observe proximal-acting elements gaining the ability to regulate distally-located genes and observe transcriptional enhancers rewiring to regulate genes present at the locus outside the segmental duplication. Many of these rewiring events are human specific. Finally, we find that segmental duplications have made outsized contributions to expanding regulatory element families functioning in immune cell types and specific brain regions, including the posterior cingulate gyrus. We speculate that placing regulatory elements in new genomic contexts primes regulatory elements for neofunctionalization, and that regulatory rewiring after segmental duplication was a common mechanism underlying gene regulatory change during human evolution.

genomics↗

bioRxiv2025

Interrogating the Regulatory Function of HAQERs during Human Cortical Development

BackgroundSequence divergence within gene regulatory elements has been proposed to play an important role in the evolution of human-specific traits, including cortical expansion. However, the mutational processes that efficiently modify gene regulatory elements and the target genes upon which they act are poorly understood. We investigated the regulatory function and origins of the fastest evolved regions in the human genome, termed Human Ancestor Quickly Evolved Regions (HAQERs), in their native genomic context during human cerebral cortex development. ResultsWe identified 50 HAQERs with accessible chromatin in developing human cortex, largely arising from previously unconstrained ancestral sequences. To test the necessity of these HAQERs for gene regulation, we established an all-in-one CRISPRi lentiviral vector and linked 26 HAQERs to nearby target genes across cell types and Wnt pathway activation contexts. Rapid gains of CpGs distinguished HAQERs active during cortical development and displaying human-specific epigenomic marks. As a high density of CpG sites can drive formation of permissive chromatin, we identified 107 HAQERs with at least 17 human-specific CpG gains per kb, termed HAQER CpG Beacons. These HAQERs emerged via contributions from GC-biased gene conversion (gBGC) with evidence for selection preferentially fixing CpG sites. Notably, the CHL1 and DPP10 loci, both implicated in human neurological disorders, each harbored two gene-linked HAQER CpG Beacons. ConclusionsOur findings reveal HAQER target genes and support a model where gBGC and natural selection jointly drive regulatory-altering CpG variants to fixation, forging regulatory innovations in the human cortex.

evolutionary biology↗

bioRxiv2025

Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans

Summary Humans exhibit significant phenotypic differences from other great apes, yet pinpointing the underlying genetic changes has been limited by incomplete reference genomes and a reliance on single assemblies to represent a species. We aligned 20 telomere-to-telomere (T2T) assemblies spanning great ape divergence and variation to define 1,596 Consensus HAQERs (consensus human ancestor quickly evolved regions), regions that diverged rapidly between the human-chimpanzee ancestor and an ancestral node of modern humans. Unlike prior HAQER sets, Consensus HAQERs incorporate population variation, reducing the likelihood of intraspecies variation appearing as interspecies divergence. Consensus HAQERs exhibit signatures of elevated mutation rates, ancient positive selection, bivalent regulatory function, are enriched in disease-linked loci, and often emerged in previously inaccessible repetitive DNA. Through multiplex, single-cell enhancer assays, we identify HAQERs as active enhancers in the developing brain and cardiomyocytes, highlighting their potential contributions to human-specific gene regulation across multiple tissues. Highlights[bullet] Telomere-to-telomere alignments of diverse human and great ape genomes identify 1,596 Consensus HAQERs, regions of rapid sequence divergence separating human ancestors from other great apes. [bullet]Consensus HAQERs exhibit signatures of both elevated mutation rates and ancient positive selection. [bullet]HAQERs are enriched in bivalent regulatory elements and disease-linked loci. [bullet]Multiplex, single-cell gene regulatory assays identify HAQERs as enhancers in the developing heart and brain.

genomics↗

bioRxiv2025

Genome Sequence of a Marine Threespine Stickleback (Gasterosteus aculeatus) from Rabbit Slough in the Cook Inlet

The Threespine Stickleback, Gasterosteus aculeatus, is an emerging model system for understanding the genomic basis of vertebrate adaptation. A strength of the system is that marine populations have repeatedly colonized freshwater environments, serving as natural biological replicates. These replicates have enabled researchers to efficiently identify phenotypes and genotypes under selection during this transition. While this repeated adaptation to freshwater has occurred throughout the northern hemisphere, the Cook Inlet in south-central Alaska has been an area of focus. The freshwater lakes in this area are being studied extensively and there is a high-quality freshwater reference assembly from a population in the region, Bear Paw Lake. Using a freshwater reference assembly is a potential limitation because genomic segments are repeatedly lost during freshwater adaptation. This scenario results in some of the key regions associated with marine-freshwater divergence being absent from freshwater genomes, and therefore absent from the reference assemblies. It may also be that isolated freshwater populations are more genetically diverged, potentially increasing reference biases. Here we present a highly-continuous marine assembly from Rabbit Slough in the Cook Inlet. All contigs are from long-read sequencing and have been ordered and oriented with Hi-C. The contigs are anchored to chromosomes and form a 454 Mbp assembly with an N50 of 1.3 Mbp, an L50 of 95, and a BUSCO score over 97%. The organization of the chromosomes in this marine individual is similar to existing freshwater assemblies, but with important structural differences, including the 3 previously known inversions that repeatedly separate marine and freshwater ecotypes. We anticipate that this high-quality marine assembly will more accurately reflect the ancestral population that founded the freshwater lakes in the area and will more closely match most other populations from around the world. This marine assembly, which includes the repeatedly deleted segments and offers a closer reference sequence for most populations, will enable more comprehensive and accurate computational and functional genomic investigations of Threespine Stickleback evolution.

genomics↗

bioRxiv2023

Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological.

genomics↗

bioRxiv2021

Evolution of stickleback spines through independent cis-regulatory changes at HOXDB

Understanding the genetic mechanisms leading to new traits is a fundamental goal of evolutionary biology. We show that HOXDB regulatory changes have been used repeatedly in different stickleback fish species to alter the length and number of bony dorsal spines. In Gasterosteus aculeatus, a variant HOXDB allele is genetically linked to shortening an existing spine and adding a spine. In Apeltes quadracus, a variant allele is associated with lengthening an existing spine and adding a spine. The alleles alter the same conserved non-coding HOXDB enhancer by diverse molecular mechanisms, including SNPs, deletions, and transposable element insertions. The independent cis-acting regulatory changes are linked to anterior expansion or contraction of HOXDB expression. Our findings support the long-standing hypothesis that natural Hox gene variation underlies key morphological patterning changes in wild populations and illustrate how different mutational mechanisms affecting the same region may produce opposite gene expression changes with similar phenotypic outcomes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/472698v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@8e6675org.highwire.dtl.DTLVardef@e89e13org.highwire.dtl.DTLVardef@1e1f1dcorg.highwire.dtl.DTLVardef@cdb6f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2018

Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution

Direct comparisons of human and non-human primate brain tissue have the potential to reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is largely inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. First, we systematically evaluated the fidelity of organoid models to primary human and macaque cortex, finding organoid models preserve gene regulatory networks related to cell types and developmental processes but exhibit increased metabolic stress. Second, we identified 261 genes differentially expressed in human compared to chimpanzee organoids and macaque cortex. Many of these genes overlap with human-specific segmental duplications and a subset suggest increased PI3K/AKT/mTOR activation in human outer radial glia. Together, our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.

developmental biology↗

bioRxiv2018

Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia

Bipolar disorder (BD) and schizophrenia (SCZ) are highly heritable diseases that affect over 3% of individuals worldwide. Genomewide association studies have strongly and repeatedly linked risk for both of these neuropsychiatric diseases to a 100 kb interval in the third intron of the human calcium channel gene CACNA1C. However, the causative mutation is not yet known. We have identified a novel human-specific tandem repeat in this region that is composed of 30 bp units, often repeated hundreds of times. This large tandem repeat is unstable using standard polymerase chain reaction and bacterial cloning techniques, which may have resulted in its incorrect size in the human reference genome. The large 30-mer repeat region is polymorphic in both size and sequence in human populations. Particular sequence variants of the 30-mer are associated with risk status at several flanking single nucleotide polymorphisms in the third intron of CACNA1C that have previously been linked to BD and SCZ. The tandem repeat arrays function as enhancers that increase reporter gene expression in a human neural progenitor cell line. Different human arrays vary in the magnitude of enhancer activity, and the 30-mer arrays associated with increased psychiatric disease risk status have decreased enhancer activity. Changes in the structure and sequence of these arrays likely contribute to changes in CACNA1C function during human evolution, and may modulate neuropsychiatric disease risk in modern human populations.

genetics↗