Person: Boettger, Linda M.
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Boettger
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Linda M.
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Boettger, Linda M.
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Publication The Genetic Basis of Phenotypic Convergence in Beach Mice: Similar Pigment Patterns but Different Genes(Oxford University Press (OUP), 2008) Steiner, C. C.; Rompler, H.; Boettger, Linda M.; Schoneberg, T.; Hoekstra, HopiConvergent evolution is a widespread phenomenon seen in diverse organisms inhabiting similar selective environments. However, it is unclear if similar phenotypes are produced by the same or different genes and mutations. Here we analyze the molecular mechanisms underlying convergent pigment pattern among subspecies of the beach mouse (Peromyscus polionotus) inhabiting the Gulf and Atlantic coasts of Florida. In these two geographic regions, separated by more than 300 km, “beach mice” have lighter colored coats than do their mainland counterparts, produced by natural selection for camouflage against the pale coastal sand dunes. We measured color pattern in eight beach mouse subspecies and showed that three of the Gulf Coast subspecies are more phenotypically similar to an Atlantic coast subspecies than to their Gulf Coast neighbors. However, light-colored beach mice do not form a monophyletic group. Previous results implicated a single derived amino acid change in the melanocortin-1 receptor (Mc1r) as a major contributor to pigment pattern in the Gulf Coast beach mice; despite phenotypic similarities, the derived Mc1r allele was not found in the Atlantic coast beach mouse populations. Here we show that Atlantic coast beach mice have high levels of Mc1r polymorphism but they lack unique alleles. Functional assays revealed that single amino acid mutations segregating in Atlantic coast beach mice do not cause any change in Mc1r activity compared with the activity of Mc1r from dark-colored mice. These joint results show that convergent pigment patterns in recently diverged beach mouse subspecies—whose developmental constraints are presumably similar—have evolved through a diversity of genetic mechanisms.Publication Recurring exon deletions in the haptoglobin (HP) gene associate with lower blood cholesterol levels(2016) Boettger, Linda M.; Salem, Rany M; Handsaker, Robert; Peloso, Gina; Kathiresan, Sekar; Hirschhorn, Joel; McCarroll, StevenTwo exons of the human haptoglobin (HP) gene exhibit copy number variation that affects HP multimerization and underlies one of the first protein polymorphisms identified in humans. The evolutionary origins and medical significance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from the recurring reversion of an ancient hominin-specific duplication of these exons. Though this polymorphism has been largely invisible to genome-wide genetic studies to date, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We show that these deletions, and a SNP that affects HP expression, are the likely drivers of the strong but complex association of cholesterol levels to SNPs near HP. Recurring exonic deletions in the haptoglobin gene likely enhance human health by lowering cholesterol levels in the blood.Publication Large multi-allelic copy number variations in humans(2015) Handsaker, Robert; Van Doren, Vanessa; Berman, Jennifer R.; Genovese, Giulio; Kashin, Seva; Boettger, Linda M.; McCarroll, StevenThousands of genome segments appear to be present in widely varying copy number in different human genomes. We developed ways to use increasingly abundant whole genome sequence data to identify the copy numbers, alleles and haplotypes present at most large, multi-allelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (>5 kb) mCNVs, including 3,878 duplications, of which 1,356 appear to have three or more segregating alleles. We find that mCNVs give rise to most human gene-dosage variation – exceeding sevenfold the contribution of deletions and biallelic duplications – and that this variation in gene dosage generates abundant variation in gene expression. We describe “runaway duplication haplotypes” in which genes, including HPR and ORM1, have mutated to high copy number on specific haplotypes. We describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses.Publication Complex Forms of Structural Variation in the Human Genome: Haplotypes, Evolution, and Relationship to Disease(2015-01-15) Boettger, Linda M.; MacDonald, Marcy; Ruvolo, Maryellen; Bailey, JeffreyGenomic mutations arise in many forms, varying from single base pair substitutions to complicated sets of overlapping copy number variants (CNVs). While each type of variation contributes to phenotype, complex structural variation, which contains multiple mutations, is difficult to type across many individuals and is largely omitted from genomic studies. This thesis presents methods to type complex structural variation, understand how it evolves, and integrate these complex variants into association studies to phenotypes. We focused on four structurally complex regions in the human genome. The 17q21.31 region contains an inversion, previously uncharacterized overlapping copy number variants, and SNPs that associate to the female meiotic recombination rate and female fertility1. The haptoglobin (HP) gene at chromosome 16q22.2 contains a 1.7 kb tandem duplication2, previously uncharacterized paralogous gene conversion, and nearby SNPs that associate to cholesterol levels3. The haptoglobin related gene (HPR) at chromosome 16q22.2, segregates as a multi-allelic copy number variant (mCNV) specifically in African populations. Lastly, complement component 4 (C4) at chromosome 6p21.3, contains a length polymorphism, paralogous sequence variation, and copy number variation segregating in humans and non-human primates4. We developed methods to characterize the complex structural variation in each of these four regions, type the variation at the population level and integrate it into association studies. Briefly, we determined the breakpoints of each individual structural variant, typed each variant in a population cohort, and learned which variants segregate together through trio inheritance patterns. Once these structural haplotypes were defined, we phased them with surrounding SNP haplotypes and used this data as a reference panel for imputation into disease cohorts, and to better understand their evolutionary history. We found that two overlapping duplications in the 17q21.31 region rose rapidly and independently to high frequency within European populations, and may account for the regional association to female fertility and the female meiotic recombination rate. We also found that a recurrent deletion in the HP gene associates to total cholesterol and LDL cholesterol levels. The methods developed in this thesis enable the integration of structurally complex variation into future association studies so that we can begin to understand their effects on phenotypes.