731 research outputs found
Evan E. Eichler
No full textDes de 2005 és investigador de l'Institut Mèdic Howard Hughes i professor adjunt del deptartament de Ciències del Genoma de la Universitat de Washington, Seattle, (Washington). El professor Eichler es va doctorar en Genètica molecular Baylor al College of Medicine, Houston, (Texas), als Estats Units. Actualment, les seves àrees de recerca es centren en la duplicació genòmica seguida d?una mutació adaptativa que es considera una de les forces primàries per a l'evolució de la nova funció. L'objectiu a llarg termini de la seva investigació consisteix a entendre l'evolució, la patologia i els mecanismes de la duplicació dels gens i la transposició del DNA dins el genoma humà.Desde el 2005 es investigador del Instituto Médico Howard Hughes y profesor adjunto del Departamento de Ciencias del Genoma del la Universidad de Washington, Seattle, (Washington). El profesor Eichler se doctoró en Genética molecular Baylor al College of Medicine, Houston, (Texas), en los Estados Unidos. Actualmente, sus áreas de investigación se centran en la duplicación genómica seguida de una mutación adaptativa que se considera una de las fuerzas primarias para l'evolución de la nueva función. El objetivo a largo plazo de su investigación consiste a entender l'evolución, la patología y los mecanismos de la duplicación de los genes y la transposición del DNA dentro el genoma humano
Acronirmus Eichler 1953
No full textAvailability of Acronirmus Eichler, 1953 Mey (2017: 91) argues that the name Acronirmus Eichler, 1953 is not taxonomically available, claiming that the correct name for that genus-group is Hirundiniella Carriker, 1963. His argument is based on the lack of a type species designation in the original description of Acronirmus by Eichler (1953), as required by Article 13.3 of the Code (1999). There is no doubt that Acronirmus Kéler, 1939 is unavailable because, although a type species is designated by monotypy (Article 68.3 of the Code 1999), Kéler (1939) did not include a description of the genus. As a result, Hopkins & Clay (1952: 20) regarded Acronirmus as a nomen nudum. However, Eichler (1953) published the name Acronirmus again, but in an independent publication; thus, Eichler, 1953 became the author and publication date for Acronirmus. Eichler (1953) included a description of the genus and listed a single species under it, i.e. Acronirmus buettikeri Eichler, 1953, which he described including the designation of a holotype, thus making the name available. In a comparative section of his paper, Eichler (1953) also indicated that he considered Acronirmus gracilis (Burmeister, 1838) a member of this genus. However, only Ac. buettikeri was described and illustrated by Eichler (1953). Carriker (1963) also correctly regarded “ Acronirmus Kéler, 1939 ” as a nomen nudum, but failed to notice that Eichler’s (1953) publication of Acronirmus is independent and described the new genus Hirundiniella for the lice that are now placed in Acronirmus Eichler, 1953. Price et al. (2003) considered Ac. buettikeri to be the type species of Acronirmus by monotypy. Gustafsson & Bush (2017) agreed with this assessment, but erroneously stated that the type species of Acronirmus was Ac. buettikeri by original designation. Considering that Eichler (1953) only listed a single species explicitly, described and illustrated it by referring to examined specimens, we agree with Price et al. (2003) in considering Acronirmus to be validly described by Eichler (1953). Eichler’s (1953) inclusion of Ac. gracilis in the short comparative section, without mentioning characters of this species, does not, in our opinion, invalidate the designation of Ac. buettikeri as the type species by monotypy.Published as part of Gustafsson, Daniel R., Bush, Sarah E. & Palma, Ricardo L., 2019, The genera and species of the Brueelia - complex (Phthiraptera: Philopteridae) described by Mey (2017), pp. 252-284 in Zootaxa 4615 (2) on page 254, DOI: 10.11646/zootaxa.4615.2.2, http://zenodo.org/record/324468
Centromere destiny in dicentric chromosomes: New insights from the evolution of human chromosome 2 ancestral centromeric region
No full textDicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process
Turdinirmus Eichler 1951
No full textTurdinirmus Eichler, 1951 Nirmus Nitzsch, 1818: 291 (in partim). Brueelia Kéler, 1936a: 257 (in partim). Turdinirmus Eichler, 1951b: 41. Turdinirmus Eichler, 1952: 78. Type species. Nirmus merulensis Denny, 1842: 51, by original designation. Diagnosis. Turdinirmus is superficially similar to Turdinirmoides n. gen. in general habitus and preantennal structure, but Turdinirmoides (Fig. 177) lacks pos and pns, which are present in Turdinirmus (Figs 184, 191). In addition, the marginal carina may be interrupted laterally in Turdinirmus (not illustrated) where the dorsal preantennal suture reaches the lateral margin of the head, but this is not the case in Turdinirmoides (Fig. 177). In Turdinirmoides there is no displaced section of the marginal carina at the osculum, whereas in Turdinirmus (Figs 184, 191) this is present as a distinct sinuous thickening of the dorsal anterior plate, similar to Resartor n. gen. (Fig. 163) or Ceratocista n. gen. (Fig. 155). Male and female genitalia also differ, as explained in the diagnosis of Turdinirmoides (see above). Turdinirmus is also superficially similar to Maculinirmus, and the abdominal chaetotaxy of these two genera (Table 2) is identical. Other characters shared by Maculinirmus and Turdinirmus include: dorsal preantennal sutures reaches the ads in both Turdinirmus (Figs 184, 191) and Maculinirmus (Figs 198, 205), and reach or nearly reach the dsms and the lateral margin of the head, but does not separate the dorsal anterior plate from the main head plate medianly, and does not entirely interrupt the marginal carina laterally; pos and pns present (Figs 184, 191, 198, 205); female subgenital plate of both Maculinirmus (Figs 202, 209) and Turdinirmus (Figs 188, 195) approach, but do not reach, the vulval margin, and in neither genus does it form a cross-piece; fI-v4 is absent in both genera; at least some sternal plates of both sexes have more than one sts on each side (Figs 182–183, 189–190, 196–197, 203–204). These two genera can be separated by the following characters: the sinuous ridge of the dorsal anterior plate found in Turdinirmus (Figs 182, 189) is absent in Maculinirmus (Figs 198, 205); the large, angular temples seen in some Turdinirmus (e.g. Tu. australissimus n. sp., Fig. 191) are never seen in Maculinirmus (Figs 198, 205); marginal temporal carina in Maculinirmus is always slender (Figs 198, 205), whereas in Turdinirmus it is always wide and irregular (Figs 184, 191); female tergopleurite XI is absent or so small and pale that it cannot be seen in Maculinirmus (Figs 197, 204), whereas in Turdinirmus (Figs 183, 190) tergopleurite IX+X is fused with tergopleurite XI; parameral heads are folded into U-shapes in Maculinirmus (Figs 201, 208), but not in Turdinirmus (Figs 187, 194); mesosomal lobes in Maculinirmus are rounded and marginal thickenings are either vague (Fig. 199) or absent (Fig. 206), whereas in Turdinirmus the lobes are more angular with a distinct marginal thickening (Figs 185, 192). Description. Both sexes . Head trapezoidal (Fig. 184) to concave-dome shaped (Fig. 191). Marginal carina broad, interrupted at least submedianly, but may be interrupted laterally as well (not illustrated). Hyaline margin continuous with dorsal preantennal suture reaching ads and reaching or nearly reaching dsms, extending median to ads but not completely separating dorsal anterior plate from main head plate. Dorsal anterior plate with sinuous thickening near posterior end, which may be displaced section of marginal carina at osculum. Ventral carinae diffuse anterior to pulvinus, and not clearly continuous with marginal carina. Ventral anterior plate present, crescent-shaped. Head setae as in Figs 184, 191. Preantennal nodi distinct. Coni small. Antennae monomorphic; mts 3 only long setae. Temporal carinae not clearly visible. Marginal temporal carina broad. Gular plate triangular with concave margins. Prothorax (Figs 182–183, 189–190) rectangular; ppss on postero-lateral corner. Proepimera with hook- or hammer-shaped median ends. Pterothorax pentagonal; lateral margins divergent; posterior margin convergent to broadly rounded median point. Meso- and metasterna not fused; 1 seta on postero-lateral corner on each side of each plate. Metepisterna with large, blunt median ends. mms widely interrupted medianly. Leg chaetotaxy as in Fig. 25, except fI-v4, fI-p2 absent. Abdomen (Figs 182–183, 189–190) oval. Abdominal chaetotaxy as in Table 2. Tergopleurites rectangular; tergopleurites II–IX+X in male and tergopleurites II–VIII in female narrowly divided medianly; tergopleurite IX+X fused to tergopleurite XI in female. Sternal plates rectangular, not approaching pleurites. Pleural incrassations wide. Re-entrant heads large, elaborate. Male subgenital plate trapezoidal, reaching posterior end of abdomen. Female subgenital plate pentagonal (Fig. 188) to triangular (Fig. 195), approaching vulval margin. No cross-piece present. Vulval margin (Figs 188, 195) with slender vms, numerous thorn-like vss; vos follows lateral margins of subgenital plate; distal vos median to vss. Basal apodeme trapezoidal (Fig. 185) to rounded with mid-length constriction (Fig. 192), distal half with transverse arch. Proximal mesosome flattened, differing in shape among species. Gonopore (Figs 186, 193) open distally and proximally, as parallel or converging thickenings. Mesosomal lobes wide, short, angular or rounded. Marginal thickenings of lobes follow margin for entire length. Up to 3 pmes visible lateral to gonopore. Parameral heads (Figs 187, 194) bifid, not folded into horseshoe-shapes. Parameral blades broadly curved; pst1 sensillus, submarginal or central; pst2 microseta, on lateral margin near distal tip. Host distribution. Turdidae. Geographical range. Throughout Old World. Remarks. No representative of Turdinirmus was included in the phylogeny of Bush et al. (2016), but the structure of the preantennal area and the male genitalia suggest that the genus may be close to Maculinirmus or Turdinirmoides. Martín-Mateo (2009: 339) claimed that no description or indication was included when Eichler (1951b) named this genus, making the name unavailable until Złotorzycka (1964a) provided a description. Eichler (1951b: 13) did, however, state that the group (the “ viscivori - Typ sensu meo”) have a characteristic head shape and share some other characteristics with the type species, Tu. merulensis. Under the entry for this species, Eichler (1951b: 15) states that Tu. merulensis has a characteristic “docophorid” head shape, providing an illustration of the head (Eichler 1951b: 16, fig. 15) showing the characteristic angular temples, broad carinae, and hints at the dorsal preantennal suture characteristic of the genus. Złotorzycka (1964a: 267) mentions only the habitus, the size (“enormous” for a “Brueeliinae”) and that, like Penenirmus s. l., Turdinirmus has an interrupted marginal carina. This does not provide a more definite description than Eichler’s (1951b); we therefore retain Eichler (1951b) as author of Turdinirmus. As an additional note, Eichler (1952: 78) described the genus as new for a second time, but did not provide any additional characters. It is unclear whether this description is based on the same material or not, as Eichler (1952) does not refer to any specimens. Złotorzycka (1964a, 1997) disagreed with Hopkins & Clay’s (1952) synonymization of Turdinirmus with Brueelia, and Mey (1982b: 179) claimed that the genus was well separated from Brueelia, and provided some illustrations, but did not list any diagnostic characters. Most recently, Mey & Barker (2014) and Valim & Palma (2015) have considered this genus to be valid, and both recognise Eichler (1951b) as the author, but neither provides additional arguments in support of their taxonomic conclusions. Species parasitic on Zoothera spp. have more clearly angular temples than species parasitic on Turdus spp. (see Tu. merulensis, Fig. 184, and Tu. australissimus, Fig. 191), but are otherwise similar, and we do not feel this difference is sufficient to erect different species groups. Included species * Turdinirmus australissimus new species * Turdinirmus daumae (Clay, 1936: 910) [in Degeeriella] Turdinirmus eichleri Mey, 1982b: 179 Brueelia neoeichleri Price, Hellenthal & Palma, 2003: 157, new synonymy [1] * Turdinirmus merulensis (Denny, 1842: 51) [in Nirmus] Nirmus merulae Denny, 1852: 18 Nirmus mandarinus Giglioli, 1864: 23 * Turdinirmus stresemanni (Clay, 1936: 910) [in Degeeriella] * Turdinirmus zootherae (Clay, 1936: 909) [in Degeeriella] [1] Turdinirmus merulensis eichleri Mey, 1982b (= Brueelia neoeichleri Price et al. 2003), is homonymous with Brueelia eichleri Lakshminarayana, 1969, only when the two species are considered to belong to the same genus. However, we regard Brueelia eichleri Lakshminarayana as a junior synonym of Mirandofures muniae Eichler, 1957 (see Mirandofures), hence we do not consider the two homonymous species congeneric. We follow Article 59.4 (International Commission on Zoological Nomenclature 1999) and reinstate Turdinirmus eichleri Mey (1982b) as valid species.Published as part of Bush, Sarah E., 2017, Morphological revision of the hyperdiverse Brueelia - complex (Insecta: Phthiraptera: Ischnocera: Philopteridae) with new taxa, checklists and generic key, pp. 1-443 in Zootaxa 4313 (1) on pages 117-119, DOI: 10.11646/zootaxa.4313.1.1, http://zenodo.org/record/88316
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Sequence Ready Characterization of the Pericentromeric Region of 19p12
No full textCurrent mapping and sequencing strategies have been inadequate within the proximal portion of 19p12 due, in part, to the presence of a recently expanded ZNF (zinc-finger) gene family and the presence of large (25-50 kb) inverted beta-satellite repeat structures which bracket this tandemly duplicated gene family. The virtual of absence of classically defined “unique” sequence within the region has hampered efforts to identify and characterize a suitable minimal tiling path of clones which can be used as templates required for finished sequencing of the region. The goal of this proposal is to develop and implement a novel sequence-anchor strategy to generate a contiguous BAC map of the most proximal portion of chromosome 19p12 for the purpose of complete sequence characterization. The target region will be an estimated 4.5 Mb of DNA extending from STS marker D19S450 (the beginning of the ZNF gene cluster) to the centromeric (alpha-satellite) junction of 19p11. The approach will entail 1) pre-selection of 19p12 BAC and cosmid clones (NIH approved library) utilizing both 19p12 -unique and 19p12-SPECIFIC repeat probes (Eichler et al., 1998); 2) the generation of a BAC/cosmid end-sequence map across the region with a density of one marker every 8kb; 3) the development of a second-generation of STS (sequence tagged sites) which will be used to identify and verify clonal overlap at the level of the sequence; 4) incorporation of these sequence-anchored overlapping clones into existing cosmid/BAC restriction maps developed at Livermore National Laboratory; and 5) validation of the organization of this region utilizing high-resolution FISH techniques (extended chromatin analysis) on monochromosomal 19 somatic cell hybrids and parental cell lines of source material. The data generated will be used in the selection of the most parsimonious tiling path of BAC clones to be sequenced as part of the JGI effort on chromosome 19 and should serve as a model for the sequence characterization of other difficult regions of the human genom
De novo missense mutations in neurodevelopmental disorders
No full textThesis (Ph.D.)--University of Washington, 2019Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder (NDD) with a high prevalence in the US (1 in 59 children). It is commonly comorbid with other NDDs such as developmental delay (DD), intellectual disability (ID), and epilepsy (EPI). In this thesis, I examine the role of de novo missense mutations in NDDs with a goal of identifying genes and specific mutations that are candidates for pathogenicity. I characterize the aggregate signal for de novo missense mutations in 8,477 NDD cases, finding both quantitative and qualitative differences between mutations in cases and controls. I also find 40 amino acids that bear de novo substitutions in two or more unrelated individuals and develop a tool to assess the likelihood of these observations in the context of stochastic de novo events. I then use targeted sequencing to further establish the association of these recurrent mutations with disease. Upon finding the same p.Ala646Thr substitution in five cases in glutamate receptor subunit GRIA1, I carry out functional experiments that show alterations in ion flux. I also assessed clustering of de novo missense mutations as this pattern is associated with NDDs, such as Schinzel-Giedion syndrome. I used an unsupervised clustering algorithm, CLUMP, to compare the distribution of de novo missense mutations in NDD cases with private missense events in controls and found 200 genes that were significantly more clustered (p < 0.05). As this set of genes is enriched for neuronal functions, a known association of NDD risk genes, it is likely that clustering is a valid feature for identification of disease genes. With increased exome sequencing on NDD cases, I was able to assess de novo mutation burden in 10,927 cases with ASD, DD, or ID. With two different models, I found 253 total genes with more de novo mutations than expected, 123 of which have a burden of missense mutations. Protein-protein interaction and enrichment analyses of genes with a burden of mutation finds that those with a burden of truncating mutations have roles in transcription regulation while those with missense burden have roles in synaptic signaling. This same neuronal enrichment, including in the amygdala and cortex during fetal development, is seen in genes with clustered de novo missense mutations. Interestingly, the phenotypes of patients with missense mutations in a novel gene, TRRAP, segregate with mutation clustering, suggesting the biological relevance of this pattern of mutation. As burden analysis only identified some of the expected pathogenic NDD genes, I included mutations from patients with EPI to my discovery set. Novel genes identified with this addition are enriched for expression in the striatum. Targeted sequencing of these hotspots of mutation identified additional substitutions at 20 recurrent sites and established 28 new recurrent sites. Eighteen of the sites are known to be pathogenic, and some evidence supports the disease association of the remaining 30 sites. Continued assessment of genes with these patterns of mutation, as well as expansion into gene families, will help to characterize the genetic architecture of NDDs, specifically missense mutations, and provide increased understanding of brain development and pathogenesis
Genome-wide variation in human germline and postzygotic mutation rates
No full textThesis (Ph.D.)--University of Washington, 2024De novo mutations (DNMs) are new variants that arise in the parental germline or early embryo. In this dissertation, I apply long-read sequencing technology to quads and a multi-generational pedigree to discover DNMs across the genome and quantify the de novo mutation rate. First, I demonstrate that long reads enable DNM discovery in previously inaccessible regions of the genome. These newly accessible regions, largely marked by repetitive sequence, have a significantly higher mutation rate than their unique counterparts, including an approximately 66% enrichment in segmental duplications. I was able to trace the origins of DNMs to either the parental germline or early rounds of embryogenesis, revealing that at least 15% of single nucleotide DNMs arise postzygotically, a 50% increase from earlier studies. Further, I found that 60% of postzygotic mutations are transmitted to the next generation, meaning that they contribute to segregating variation in the population. Finally, I estimate the de novo mutation rate to be approximately 1.2-1.3Ã 10-8 substitutions/base pair/generation for 30 year old parents, and the postzygotic mutation rate to be approximately 0.23Ã 10-8 substitutions/base pair/generation. My analyses reveal that repetitive regions are in fact hypermutable, and that more variation arises postzygotically than previously thought. This work also lays the foundation for the next frontier in DNM discovery: comparing assembled parent and child genomes to reveal variation in the most complex and mutable parts of the genome
Evolution and diversity of hominid genomes
No full textThesis (Ph.D.)--University of Washington, 2013Copy number variants (CNVs) contribute to a substantial amount of diversity both between and among hominid species. In this thesis I set out to catalog this variation across the hominid lineage and assess its impact on the evolution of great ape species and its contribution to extant diversity. I develop methods to detect and genotype CNVs using high-throughput sequencing and demonstrate the first population scale analysis of the diversity of segmental duplications and duplicated gene families in a panel of 159 humans. I identify 56 highly population stratified genes and 23 genes that have undergone duplication specifically in the human lineage. I go on to demonstrate a resource of 4.1 million singly unique nucleotide (SUN) identifiers, which can be used to infer paralog-specific copy number and explore duplicated gene families. I next describe the sequencing of a panel of 79 wild and captive-born great apes to better understand the genetic diversity of extant great ape populations. I identify 86.5 million single nucleotide polymorphisms (SNPs) and use this resource to construct a model of great ape demography and population diversity. I outline the topology of relationships between great ape populations and the relative levels of heterozygosity among these populations. Finally, I identify 23,770 CNVs in these great ape individuals and characterize diversity both within and between species. Among these CNVs I identify the first example of a genomic disorder in a chimpanzee--a single individual with features resembling Smith-Magenis syndrome. I calculate the exact rates of duplication and deletion along each of the great ape lineages and show that an excess of deletions occurred along the chimpanzee-bonobo ancestral lineage. This excess coincides with a severe drop in the effective population size of the chimpanzee-bonobo ancestor. Analysis of recently bottlenecked great ape populations also shows an excess burden of duplications and deletions among these individuals. These results suggest that changes in effective population size may be responsible for historical shifts in the rates of duplication and deletion in the hominid lineage
Understanding the genetic basis of phenotype variability in individuals with neurocognitive disorders
No full textThesis (Ph.D.)--University of Washington, 2016-06Individuals with a diagnosis of a neurocognitive disorder, such as an autism spectrum disorder (ASD), can present with a wide range of phenotypes. Some have severe language and cognitive deficiencies while others are only deficient in social functioning. Sequencing studies have revealed extreme locus heterogeneity underlying the ASDs. Even cases with a known pathogenic variant, such as the 16p11.2 CNV, can be associated with phenotypic heterogeneity. In this thesis, I test the hypothesis that phenotypic heterogeneity observed in populations with a known pathogenic variant, such as the 16p11.2 CNV as well as that associated with the ASDs in general, is due to additional genetic factors. I analyze the phenotypic and genotypic characteristics of over 120 families where at least one individual carries the 16p11.2 CNV, as well as a cohort of over 40 families with high functioning autism and/or intellectual disability. In the 16p11.2 cohort, I assessed variation both internal to and external to the CNV critical region. Among de novo cases, I found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p=2.38x10^-11), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome, a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p=1.14x10^-2), and nine probands carrying additional CNVs disrupting autism-associated genes. In the same cohort, I assessed genome wide exonic variation, including in the 27 16p11.2 CNV critical region genes and the 3 genes that lie in the flanking segmental duplications, BOLA2, SLX1A, and SULT1A3 with the hypothesis that dosage imbalance in these genes could lead to variable phenotypes. I find an absence of variation across the critical region, compared to similarly sized regions genome-wide by average heterozygosity (2nd percentile) and Tajima’s D (3rd percentile) metrics. Among the 27 critical region genes and three duplicated genes, I find no loss of function variants in 16p11.2 CNV carriers. Our genome-wide exome analysis revealed 13 likely-gene disruptive (LGD) variants in 13 probands in autism-associated genes, which is fewer than would be expected by chance (p<10^-16) and individuals having such variants trend towards being more severely affected on FSIQ (p=0.19). To understand the genetic heterogeneity associated with high-functioning autism and intellectual disability, I assessed genetic variation observed in a cohort of 43 local families of which 29 have a diagnosis of high functioning-autism. I discovered variants in novel autism candidate genes, including LPHN1 and NUMBL, find that the high functioning autism cohort tends to have more inherited loss of function and severe missense variation per individual than low functioning cohorts (p<2.2x10^-16), but fewer de novo LGD variants per individual (p=0.007). I also find that de novo variants in high functioning cases lie in a protein-protein interaction network including proteins involved in the NOTCH signaling pathway. Our findings suggest that modifiers external to, as opposed to variants internal to the critical region, may play a role in the observed phenotypic differences observed in individuals with a 16p11.2 CNV and those with ASDs in general
Genetic etiologies of Autism Spectrum Disorder
No full textThesis (Ph.D.)--University of Washington, 2014Autism spectrum disorder (ASD) is a common, heritable neurodevelopmental disorder. In this thesis, I examine how different genetic etiologies, mutation types and specific genes contribute to the risk of ASD, and how these factors can be used to expand our understanding of the neurobiological underpinnings of ASD. I develop a new bioinformatics method (CoNIFER: Copy Number Inference from Exome Reads) to identify Copy Number Variants (CNVs) using exome sequencing data, enabling much more sensitive identification of a previously under-ascertained class of small CNVs (<100kb in size). I estimate the precision of the algorithm using 366 exomes and show that this method can be used to reliably predict both <italic>de novo</italic> and inherited rare CNVs and can predict absolute copy number for loci with fewer than eight copies. Next, I searched for disruptive, genic rare CNVs among 411 families with sporadic ASD from the Simons Simplex Collection and identified additional small genic rare CNVs compared to high-density SNP microarrays (~2x higher yield). I found that affected probands inherit more CNVs than their siblings (p=0.004; OR=1.19), and these CNVs affect more genes, are enriched for brain-expressed genes, and are transmitted preferentially from the mother. I found that the excess burden of inherited CNVs among probands is driven primarily by sib-pairs with discordant social behavior phenotypes. Next, I created a combined set of both inherited and <italic>de novo</italic> Single Nucleotide Variants (SNVs) and CNVs across 2,377 Simons Simplex Collection (SSC) ASD families, including 1,786 families with both an affected and unaffected child. I compared the burden of inherited and <italic>de novo</italic> mutations between affected and unaffected siblings and found that private inherited truncating SNV mutations in conserved genes are significantly enriched in probands (OR=1.14, p < 0.0002)-- an effect that became more pronounced with increasing gene conservation. I quantified ASD risk for <italic>de novo</italic> and inherited CNVs and SNVs by using a conditional logistic regression model. Independent from <italic>de novo</italic> mutations, private truncating SNVs and rare inherited CNVs contribute an increase in risk of 1.11 (p=0.0002) and 1.23 (p = 0.01), respectively. These results confirm a statistically independent role for inherited mutations in ASD risk and identify additional candidate genes (eg. <italic>RIMS1</italic>, <italic>CUL7</italic> and <italic>CSMD1</italic>) where inherited and <italic>de novo</italic> burden converge
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