Michael J Bamshad

University of Everett Washington, Seattle, Washington, United States

Are you Michael J Bamshad?

Claim your profile

Publications (166)1698.79 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. METHODS: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. RESULTS: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. CONCLUSIONS: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
    New England Journal of Medicine 08/2014; 371(8):733-43. · 51.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results.
    The American Journal of Human Genetics 07/2014; · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Professional recommendations for the return of results from exome and whole-genome sequencing (ES/WGS) have been controversial. The lack of clear guidance about whether and, if so, how to return ES/WGS incidental results limits the extent to which individuals and families might benefit from ES/WGS. The perspectives of genetics professionals, particularly those at the forefront of using ES/WGS in clinics, are largely unknown. Data on stakeholder perspectives could help clarify how to weigh expert positions and recommendations. We conducted an online survey of 9,857 genetics professionals to learn their attitudes on the return of incidental results from ES/WGS and the recent American College of Medical Genetic and Genomics Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Of the 847 respondents, 760 completed the survey. The overwhelming majority of respondents thought that incidental ES/WGS results should be offered to adult patients (85%), healthy adults (75%), and the parents of a child with a medical condition (74%). The majority thought that incidental results about adult-onset conditions (62%) and carrier status (62%) should be offered to the parents of a child with a medical condition. About half thought that offered results should not be limited to those deemed clinically actionable. The vast majority (81%) thought that individual preferences should guide return. Genetics professionals' perspectives on the return of ES/WGS results differed substantially from current recommendations, underscoring the need to establish clear purpose for recommendations on the return of incidental ES/WGS results as professional societies grapple with developing and updating recommendations.
    The American Journal of Human Genetics 06/2014; · 11.20 Impact Factor
  • American Journal of Medical Genetics Part A 06/2014; · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Exome sequencing and whole genome sequencing (ES/WGS) present individuals with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, it is unclear which genetic results people want to receive (i.e., what type of genetic information they want to learn about themselves) or conversely not receive, and how they want to receive or manage results over time. Very little is known about whether and how attitudes toward receiving individual results from ES/WGS vary among racial/ethnic populations. We conducted 13 focus groups with a racially and ethnically diverse parent population (n = 76) to investigate attitudes toward return of individual results from WGS. We report on our findings for non-African American (non-AA) participants. Non-AA participants were primarily interested in genetic results on which they could act or “do something about.” They defined “actionability” broadly to include individual medical treatment and disease prevention. The ability to plan for the future was both a motivation for and an expected benefit of receiving results. Their concerns focused on the meaning of results, specifically the potential inaccuracy and uncertainty of results. Non-AA participants expected healthcare providers to be involved in results management by helping them interpret results in the context of their own health and by providing counseling support. We compare and contrast these themes with those we previously reported from our analysis of African American (AA) perspectives to highlight the importance of varying preferences for results, characterize the central role of temporal orientation in framing expectations about the possibility of receiving ES/WGS results, and identify potential avenues by which genomic healthcare disparities may be inadvertently perpetuated. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2014; · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
    The American Journal of Human Genetics 04/2014; · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect co-segregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.
    Human Mutation 04/2014; · 5.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Mixed Lineage Leukemia-1 (MLL1) enzyme is a histone H3 lysine 4 (H3K4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET1 family of enzymes that include MLL1-4, and SET1d1a,b. Dimethylation of H3K4 requires a sub-complex including WDR5, RbBP5, Ash2L, and DPY-30 (WRAD), which binds to each SET1 family member forming a minimal core complex that is required for multiple lysine methylation. We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H3K4 dimethylation in a manner that is dependent on an unknown non-active site surface from the MLL1 SET domain. Recent genome sequencing studies have identified a number of human disease-associated missense mutations that localize to the SET domains of several MLL family members. In this investigation, we mapped many of these mutations onto the three-dimensional structure of the SET domain and noticed that a subset of MLL2 (KMT2D, ALR, MLL4)-associated Kabuki syndrome (KS) missense mutations map to a common solvent-exposed surface that is not expected to alter enzymatic activity. We introduced these mutations into the MLL1 SET domain and observed that all are defective for H3K4 dimethylation by the MLL1 core complex, which is associated with a loss of the ability of MLL1 to interact with WRAD or with the RbBP5-Ash2L heterodimer. Our results suggest that amino acids from this surface, which we term the Kabuki interaction surface or (KIS), are required for formation of a second active site within SET1 family core complexes.
    Journal of Molecular Biology 03/2014; · 3.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic etiology is not defined for all PCD patients. Objectives: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in PCD patients. Measurements and Main Results: We performed exome sequencing on affected sib-pair with normal ultrastructure in >85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in 9 additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in PCD patients with other gene mutations (98.3 versus 20.7 nl/min; p<0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8/16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared to 75 age- and gender-matched PCD cases (73.0 versus 61.8, FEV1 % Pred.; p=0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 +/- Hz at 25°C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function. Abstract has 250 words. Keywords: cilia, Kartagener, sequencing, mutation, RSPH1.
    American Journal of Respiratory and Critical Care Medicine 02/2014; · 11.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Over 100 human genetic disorders result from mutations in glycosylation-related genes. In 2013, a new glycosylation disorder was reported every 17 days. This trend will probably continue given that at least 2% of the human genome encodes glycan-biosynthesis and -recognition proteins. Established biosynthetic pathways provide many candidate genes, but finding unanticipated mutated genes will offer new insights into glycosylation. Simple glycobiomarkers can be used in narrowing the candidates identified by exome and genome sequencing, and those can be validated by glycosylation analysis of serum or cells from affected individuals. Model organisms will expand the understanding of these mutations' impact on glycosylation and pathology. Here, we highlight some recently discovered glycosylation disorders and the barriers, breakthroughs, and surprises they presented. We predict that some glycosylation disorders might occur with greater frequency than current estimates of their prevalence. Moreover, the prevalence of some disorders differs substantially between European and African Americans.
    The American Journal of Human Genetics 02/2014; 94(2):161-175. · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclic AMP (cAMP) production, which is important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearing-impaired family members, a nonsense mutation c.3112C>T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individuals who are homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1 has an evolutionarily conserved role in hearing and that cAMP signaling is important to hair cell function within the inner ear.
    Human Molecular Genetics 01/2014; · 7.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated genetic variants in 51 candidate genes encoding proteins that interact with HIV-1 during the virus life cycle for association with HIV-1 outcomes in an African cohort. Using a nested case-control study within a cohort of heterosexual HIV-1 serodiscordant couples, we genotyped 475 haplotype-tagging (tagSNPs) and 18 Single Nucleotide Polymorphisms (SNPs) previously associated with HIV-1 transmission and/or progression (candidate SNPs) in 51 host genes. We used logistic and Cox proportional hazards regression with adjustment for sex, age, and population stratification to detect SNP associations with HIV-1 acquisition, plasma HIV-1 set-point, and a composite measure of HIV-1 disease progression. Significance thresholds for tagSNP, but not candidate SNP, associations were subjected to Bonferroni correction for multiple testing. We evaluated 491 HIV-1 infected and 335 HIV-1 uninfected individuals for 493 SNPs, 459 of which passed quality control filters. Candidate SNP PPIA rs8177826 and haplotype tagging SNP SMARCB1 rs6003904 were significantly associated with HIV-1 acquisition risk (odds ratio [OR] = 0.14, p=0.03, and 2.11, pcorr= 0.01, respectively). Furthermore, the TT genotype for CCR5 rs1799988 was associated with a mean 0.2 log10 copies/mL lower plasma HIV-1 RNA set-point (p = 0.04). We also identified significant associations with HIV-1 disease progression for variants in FUT2 and MBL2. Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with HIV-1 outcomes in this African cohort.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2014; · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.
    The American Journal of Human Genetics 01/2014; 94(1):144-52. · 11.20 Impact Factor
  • Neurotoxicology and Teratology 01/2014; 43:78. · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective. We evaluated Toll-like receptors (TLRs) single nucleotide polymorphisms (SNPs) for associations with HIV-1 acquisition, set-point and disease progression in African couples.Methods. Seven candidate and 116 haplotype-tagging SNPs (tagSNPs) were genotyped in 504 HIV-1 infected cases, and 343 seronegative controls.Results. TLR9 1635A/G was associated with reduced HIV-1 acquisition among HIV-seronegative controls with high but not low HIV-1 exposure (odds ratio [OR]=0.7; p=0.03 and OR=0.9, p=0.5, respectively). TLR7 rs179012 and TLR2 597C/T reduced set-point; the latter modified by time since HIV-1 acquisition. TLR8 1A/G reduced disease progression.Conclusion. TLR SNPs impact HIV-1 outcomes with epidemiologic factors modifying these relationships.
    The Journal of Infectious Diseases 12/2013; · 5.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The study of genetic influences on drug response and efficacy ('Pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 African-American and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within twelve Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splice sites, and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over 3 times greater in African-American individuals as compared to Caucasians. While most of these impactful alleles are individually rare, 7.6%-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
    Human Molecular Genetics 11/2013; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nearly 50 Congenital Disorders of Glycosylation (CDG) are known, but many patients biochemically diagnosed with CDG do not have mutations in known genes. Here, we describe a sixteen year old male who was born with microcephaly, developed intellectual disability, gastroesophageal reflux and a seizure disorder. We identified a de novo variant in the X-linked SSR4 gene which encodes a protein of the heterotetrameric translocon-associated protein (TRAP) complex. The c.316delT causes a p.F106Sfs*53 in SSR4 and also reduces expression of other TRAP complex proteins. The glycosylation marker Glyc-ER-GFP was used to confirm the underglycosylation in fibroblasts from the patient. Over-expression of the wild type SSR4 allele partially restores glycosylation of the marker and of the other members of the TRAP complex. This is the first evidence that the TRAP complex, which binds to the oligosaccharyltransferase complex, is directly involved in N-glycosylation.
    Human Molecular Genetics 11/2013; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control. Infant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort. Infants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load. Among 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month [hazard ratio = 1.81, 95% confidence interval (CI) = 1.05-3.14, P = 0.033] and by 12 months (hazard ratio = 1.62, CI = 1.01-2.60, P = 0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at 1 month of age or less, at least one copy of the TLR9 1635A allele was associated with a 0.58 log10 copies/ml lower peak viral load (P = 0.002). Female infants with at least one copy of the TLR8 1G (rs3764880) variant had a 0.78 log10 copies/ml higher peak viral load (P = 0.0009) and having at least one copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log10 copies/ml higher peak viral load in female infants (P = 0.0003). In this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.
    AIDS (London, England) 09/2013; 27(15):2431-9. · 4.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.
    The American Journal of Human Genetics 09/2013; · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most mammals possess a tail, humans and the Great Apes being notable exceptions. One approach to understanding the mechanisms and evolutionary forces influencing development of a tail is to identify the genetic factors that influence extreme tail length variation within a species. In mice, the Tailless locus has proven to be complex, with evidence of multiple different genes and mutations with pleiotropic effects on tail length, fertility, embryogenesis, male transmission ratio, and meiotic recombination. Five cat breeds have abnormal tail length phenotypes: the American Bobtail, the Manx, the Pixie-Bob, the Kurilian Bobtail, and the Japanese Bobtail. We sequenced the T gene in several independent lineages of Manx cats from both the US and the Isle of Man and identified three 1-bp deletions and one duplication/deletion, each predicted to cause a frameshift that leads to premature termination and truncation of the carboxy terminal end of the Brachyury protein. Ninety-five percent of Manx cats with short-tail phenotypes were heterozygous for T mutations, mutant alleles appeared to be largely lineage-specific, and a maximum LOD score of 6.21 with T was obtained at a recombination fraction (Θ) of 0.00. One mutant T allele was shared with American Bobtails and Pixie-Bobs; both breeds developed more recently in the US. The ability of mutant Brachyury protein to activate transcription of a downstream target was substantially lower than wild-type protein. Collectively, these results suggest that haploinsufficiency of Brachyury is one mechanism underlying variable tail length in domesticated cats.
    Mammalian Genome 08/2013; · 2.42 Impact Factor

Publication Stats

11k Citations
1,698.79 Total Impact Points

Institutions

  • 2007–2014
    • University of Everett Washington
      Seattle, Washington, United States
    • Center for Human Genetics Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2006–2014
    • University of Washington Seattle
      • • Department of Genome Sciences
      • • Department of Pediatrics
      Seattle, Washington, United States
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2013
    • Massachusetts General Hospital
      • Cutaneous Biology Research Center
      Boston, MA, United States
  • 2012–2013
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • Seattle Children’s Research Institute
      Seattle, Washington, United States
  • 2009–2013
    • Seattle Children's Hospital
      • Department of Pediatrics
      Seattle, Washington, United States
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1995–2009
    • University of Utah
      • • Department of Human Genetics
      • • Department of Pediatrics
      Salt Lake City, UT, United States
  • 2005
    • University of California, San Francisco
      • Department of Pediatrics
      San Francisco, CA, United States
  • 2002–2005
    • The University of Arizona
      Tucson, Arizona, United States
  • 1999–2005
    • University of Texas Health Science Center at San Antonio
      • Division of Hospital Medicine
      San Antonio, TX, United States
  • 2001
    • Salt Lake City Community College
      Salt Lake City, Utah, United States
    • Andhra University
      • Department of Anthropology
      Vizag, Andhra Pradesh, India
    • Paediatric Hospital Dr. Juan P. Garrahan
      Buenos Aires, Buenos Aires F.D., Argentina
  • 1998
    • Shriners Hospitals for Children
      Tampa, Florida, United States
    • Rice University
      • Department of Statistics
      Houston, TX, United States