No description available.

I explore the genetic and environmental basis of inheritance using modern techniques, in particular high-density genotyping arrays, and older techniques, in particular family history, to explore some longstanding questions about the way we inherit complex traits. Using pedigree data and the parent-offspring regression technique, I estimate narrow sense heritability (h2) of human lifespan in 20th Century Scotland as 0.16, lower than commonly cited studies in other populations. I also observe similar concordance between spouses as between parents and offspring - suggesting my estimate of heritability may include significant within-family environment effects and thus should be considered an upper bound. Using genome-wide array data to identify runs of homozygosity, from 150 cohorts across the world and up to 350,000 subjects per trait, I show that cognitive function and body size are associated with the total length of genome-wide runs of homozygosity. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of homozygosity on blood pressure and low-density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. An association between genome-wide homozygosity and complex traits arises due to directional dominance. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases have not. The analysis of less common single nucleotide polymorphism (SNP) variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association, whilst avoiding false positives. I show that addition of 100 population-specific exome sequences to 1,000 genomes global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1–10%). The imputation improvement corresponds to an increase in effective sample size of 28–38%, for SNPs with a minor allele frequency in the range 1–3%. Inheritance of complex traits remains a field wide open for discovery, both in determining the balance between nature and nurture and discovery of the specific mechanisms by which DNA causes variation in these traits, with the prospect of such discoveries illuminating biological pathways involved and, as knowledge deepens, facilitating prediction.

Inbreeding results in increased levels of homozygosity for deleterious recessive alleles, leading to increased incidence of monogenic disease in inbred families. It has also been suggested that inbreeding increases the risk of diseases such as cancer and heart disease, implying a role for the combined effects of many recessive alleles distributed across the genome. A better understanding of the links between inbreeding, homozygosity and disease is therefore of interest to those concerned with understanding the genetic architecture of complex disease. A homozygous genotype is defined as autozygous if both alleles originate from the same ancestor. Quantifying inbreeding involves quantifying autozygosity. A new, observational method of quantifying autozygosity using genomic data is developed here. Based on runs of homozygosity (ROH), this approach has a sound theoretical basis in the biological processes involved in inbreeding. It is also backed by strong empirical evidence, correlating strongly with pedigree-derived estimates of inbreeding and discriminating well between populations with different demographic histories. ROH are a signature of autozygosity, but not necessarily autozygosity of recent origin. Short ROH are shown to be abundant in demonstrably outbred individuals and it is suggested that this is a source of individual genetic variation which merits investigation as a disease risk factor, although denser genotype scans than those used in the present study are required for the reliable detection of very short ROH. In the absence of such dense scans, it is suggested that ROH longer than 1 or 1.5 Mb be used to estimate the effects of inbreeding on disease or quantitative physiological traits (QT), and that a simple measure of homozygosity be used to investigate overall recessive effects. Evidence for recessive effects on 13 QT important in cardiovascular and metabolic disease was investigated in 5 European isolate populations, characterised by heightened levels of inbreeding. A significant decrease in height was associated both with increased homozygosity and (to a lesser extent) with increased ROH longer than 5 Mb (i.e. inbreeding) estimated using a 300,000 SNP panel. No evidence was found for recessive effects on any of the other QTs. Evidence for recessive effects on colorectal cancer risk were investigated in two outbred case control samples typed with a 500,000 SNP panel. Cases were significantly more homozygous and had more of their genome in short ROH than did controls. Cases were significantly more homozygous than controls even when inbred individuals were removed from the sample. There was also some evidence of an inbreeding effect, with inbred subjects having slightly significantly higher odds of colorectal cancer than outbred subjects. This study provides evidence of recessive effects on a common, complex disease in outbred populations and on height in both inbred and outbred populations and shows that such effects are not solely attributable to increased levels of homozygosity resulting from recent inbreeding. Individual variation among outbred individuals in the proportion of the genome that is homozygous may be important in disease risk. The development of denser genotype scans will facilitate better enumeration of short ROH in outbred individuals so that these can be properly enumerated and investigated as a disease risk factor.

Positive natural selection is recognized as the driving force underneath evolution. One of the surest signatures of recent positive selection is a local elevation of advantageous allele frequency and linkage disequilibrium (LD). This dissertation proposes a new test statistic to detect excess homozygosity based on a simple counting measure, which serves as a surrogate indicator of recent positive selection. Three tests are developed upon the new measure: (a) an extended genotype-based homozy- gosity test (EGHT), (b) a hidden Markov model test (HMMT), and (c) an extended haplotype-based homozygosity test (EHHT). The null hypotheses of all three tests assume random mating and Hardy-Weinberg equilibrium (HWE). They differ in how to treat LD under H0 . The EGHT assumes linkage equilibrium (LE) besides HWE while the EHHT allows arbitrary multi-locus LD. The HMMT stands between these two extremes and assumes pairwise but no higher-order disequilibrium interactions. We first conduct simulation study to compare the three score tests and verify that the EHHT is the most conservative one. We compare the performance of the EHHT with the prevailing detection methods and the EHHT has higher or similar power. We also evaluate the impact of simple demographic history on the EHHT and the simulation study suggests that the EHHT is resistant to the false-positive confounders resulting from simple demographic models. After extensive simulation studies, all three tests are then applied on HapMap Phase II data and we are able to replicate findings reported in the literature. We can also identify new candidate regions that may undergo recent selection through a set of filtering criteria including highest EHHT scores, high derived allele frequency and large population differentiation. Finally, we propose a cross-population comparison test statistic to detect chromosome regions in which there is no significant excess homozygosity in one population but homozygosity remains high in another population.

Submitted by Ana Cristina Herrera Rios (anacristinah@gmail.com) on 2018-09-06T21:12:03Z No. of bitstreams: 1 Herrera_a_ma_jabo.pdf: 1549720 bytes, checksum: cc3a9f221086386bf628813bbc967443 (MD5) / Approved for entry into archive by Neli Silvia Pereira null (nelisps@fcav.unesp.br) on 2018-09-10T16:57:12Z (GMT) No. of bitstreams: 1 herrerarios_ac_dr_jabo.pdf: 1549720 bytes, checksum: cc3a9f221086386bf628813bbc967443 (MD5) / Made available in DSpace on 2018-09-10T16:57:12Z (GMT). No. of bitstreams: 1 herrerarios_ac_dr_jabo.pdf: 1549720 bytes, checksum: cc3a9f221086386bf628813bbc967443 (MD5) Previous issue date: 2018-07-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O uso intensivo de biotecnologias reprodutivas tem feito com que se eleve a taxa de nascimento de progênies com maior grau de parentesco (maior taxa de nascimento de meio-irmãos e irmãos completos). Assim, o conhecimento sobre o coeficiente da endogamia média do rebanho torna-se relevante para a eficiência do sistema de produção. Com o advento da genômica, o coeficiente de endogamia (F) pode ser estimado com base na informação de milhares de marcadores do tipo polimorfismos de base única (SNPs), espalhados por todo o genoma. No presente estudo, informações de 3.785 animais da raça Nelore (1,760 machos e 2,025 fêmeas) genotipados para 777.962 SNPs do BovineHD BeadChip (Illumina Inc., San Diego, CA, USA) foram utilizadas com o objetivo de avaliar a taxa de endogamia em rebanhos comerciais da raça Nelore, bem como investigar o seu efeito (depressão endogâmica) sobre a expressão fenotípica de características reprodutivas (idade ao primeiro parto (IPP), ocorrência de prenhez precoce (OPP) e reconcepcão de novilhas (REC)). A estimativa do valor de F, bem como da depressão endogâmica, foi feita utilizando diferentes metodologias: (i) matriz de parentesco genômica com frequências alélicas obtidas da população base (FG); (ii) matriz de parentesco genômica com frequências alélicas fixadas em 0,5 (FGRM); (iii) com base no excesso de SNPs em homozigose (FSNP); e (iv) corrida de homosigose (FROH). Os resultados da corrida de homosigose também foram utilizados para identificar os padrões (tamanho e distribuição) dos segmentos ROH na raça Nelore bem como para identificar ilhas de homosigose (segmentos ROH compartilhados por mais de 50% da população). Foram identificados 210.636 segmentos ROH distribuídos nos 29 autossomos e cinco ilhas de homozigose localizadas nos cromossomos 5, 7, 12, 21 e 26, nas quais 43 genes foram identificados. Alguns destes genes (INHBE, INHBC, STAT6, FGF8 e DPCD) foram previamente associados com caracteristicas reproductivas, de crescimento, resposta inmume e adaptabilidade em bovinos. As médias para o coeficiente de endogamia calculado com base nas diferentes abordagens foram: -0,0006 (FG), 0,4376 (FGRM), 0,5500 (FSNP) e 0,0590 (FROH). As correlações foram ente baixas FG-FSNP (-0,28), FG-FGRM (-0,20), FG-FROH (0,21), a moderadas FROH-FSNP (0,68), FROH-FGRM (0,72) e fortemente alta para FSNP-FGRM (0,99). O valor médio de F variou de acordo com a metodologia utilizada. O valor extremamente alto do FSNP denota que este método tende a superestimar as taxas de endogamia. Independentemente do método utilizado para obter os valores de F, foi verificado que o aumento de 1% no coeficiente de endogamia médio do rebanho influenciou desfavoravelmente a média das características reprodutivas avaliadas. / The intensive use of reproductive biotechnologies has increased the birth rate of progenies with high degree of relationships (higher birth rate of half- and full-sibs). Thus, the control of herd inbreeding becomes relevant for the efficiency of the production system. With genomics, the inbreeding coefficient can be estimated using thousands of single nucleotide polymorphisms (SNPs), spread throughout the genome. In the present study, information of 3,785 Nelore animals (1,760 males and 2,025 females) genotyped with 777,962 SNP markers of BovineHD BeadChip (Illumina Inc., San Diego, CA, USA) was used with the objective of evaluating the inbreeding rates of Nelore commercial herds, as well as to investigate the effects of inbreeding (inbreeding depression) on the phenotypic expression of reproductive traits (age at first calving (AFC), heifer early pregnancy (EP), and heifer rebreeding (HR)). The inbreeding coefficient (F) and inbreeding depression were estimated based on (i) genomic relationship matrix considering allele frequencies estimated from the base population (FG); (ii) genomic relationship matrix considering allele frequencies fixed at 0.5 (FGRM); (iii) excess of homozygous SNPs (FSNP); and (iv) runs of homozygosity (FROH). The runs of homozygosity results were also used to identify the pattern (size and distribution) of ROH segments as well as to identify ROH islands (ROH segments shared by more than 50% of the population). In total, there were identified 210,636 ROH segments and five ROH Islands located on the chromosomes 5, 7, 12, 21 and 26, in which 43 annotated genes were identified. Some of these genes (INHBE, INHBC, STAT6, FGF8 and DPCD) were previously associated with reproduction and growth traits, inmume response and adaptability in cattle. The average inbreeding calculated based on different approaches were -0.0006 (FG), 0.4376 (FGRM), 0.5500 (FSNP) e 0.0590 (FROH). These correlations ranged from low FG-FSNP (-0.28), FG-FGRM (-0.20), FG-FROH (0.21), to moderated FROH-FSNP (0.68), FROH-FGRM (0.72) and extremely high FSNP-FGRM (0.99). The average population inbreeding coefficient ranged according to the method used. The extremely high value of FSNP indicates that this approach tend to overestimate the inbreeding rates. Independently of the method used to obtain the F values, it was verified that the increase of 1% in the average herd inbreeding unfavorably influenced the mean value of the evaluated reproductive traits. / FAPESP#2009/16118-5

Plant breeding is focused on selection of new genotypes with improved traits. Conventional methods based on hybridization and those based on biotechnology (somatic hybridization, genetic transformation, ploidy manipulation, etc.) are used to create novel genetic variations. Biotechnology provides powerful tools for plant breeding, for instance, haploid technology allows achievement of homozygous lines from heterozygous parents in one step, which reduces significantly the time required by conventional methods. Concerning woody species, characterized by self-incompatibility, long juvenile period and high degree of heterozygosity, this technique is the only way to get homozygous lines. Haploid plants are of great interest for breeding and genomic studies, being used in mutation research, genetic analysis, genome mapping and gene transfer. Gametic embryogenesis, based on cellular totipotency, produces an embryo from an immature gamete, by switching its developmental pathway from gametophytic to sporophytic. This research is focused on inducing gametic embryogenesis in two important Mediterranean fruit crops: almond (Prunus dulcis Mill.) via in vitro anther culture and mandarin (Citrus reticulata Blanco) via isolation and microspore culture. Also ploidy manipulation was applied to loquat (Eriobotrya japonica (Thunb.) Lindl.) for getting genotypes whit different ploidy levels. The experiments were carried out through years 2014, 2015 and 2016 at the 'Università degli Studi di Palermo' (UNIPA) as well as at the 'Instituto Valenciano de Investigaciones Agrarias' (IVIA). Regarding the almond anther culture, formation of calli and production of embryos was achieved through the direct embryogenesis route. On then other hand, early embryo regeneration is reported, for the first time, from isolated microspore culture of mandarin, 'Mandarino Tardivo di Ciaculli'. Our results report the evidence of gametic embryogenesis and the production of homozygous regenerants in almond and mandarin, two species extremely recalcitrant to microspore embryogenesis. However, the results are affected by many factors that need further studies to better understand the embryogenic development and to increase the rate of embryo achievement. Moreover, another biotechnological tool (ploidy manipulation) was also applied for implementing the IVIA loquat breeding program. Polyploid plants are of great interest in this species, due to its potential for producing seedless genotypes via direct use of triploids or crosses between tetra and diploids. Aimed at obtaining new loquat genotypes, with different ploidy levels (polyploids), colchicine was applied to seeds before germination, to induce chromosome duplication. A total of three triploids (3x) and one tetraploid (4x) were obtained. / La mejora genética tiene como objetivo la selección de nuevos genotipos con mejores características. Los métodos de mejora convencional basados en hibridaciones y aquellos basados en Biotecnología (hibridación somática, transformación genética, manipulación de la ploidía, etc.) se utilizan para obtener nueva variación genética. La Biotecnología proporciona herramientas poderosas en mejora genética, por ejemplo, la obtención de haploides permite obtener líneas homocigotas en un solo paso, disminuyendo significativamente el tiempo requerido usando métodos convencionales. Respecto a especies leñosas, caracterizadas por autoincompatibilidad floral, largo período juvenil y alto grado de heterocigosidad, esta técnica es el único método de obtención de líneas homocigotas. Los genotipos haploides tienen un alto interés en estudios genómicos, siendo utilizados en estudios de mutaciones, análisis genéticos, mapeo genético y transferencia genética. Este estudio tiene como objetivo la inducción de embriogénesis gamética en dos especies mediterráneas muy importantes: el almendro (Prunus dulcis Mill.) por medio de cultivo in vitro de anteras y el mandarino (Citrus reticulata Blanco) por medio de aislamiento de microesporas. Además, se ha estudiado la obtención de poliploides en níspero (Eriobotrya japonica (Thunb.) Lindl.) con el objetivo de obtener genotipos con diversos niveles de ploidía. Los experimentos se llevaron a cabo en los años 2014, 2015 y 2016 en la 'Università degli Studi di Palermo' (UNIPA) y en el 'Instituto Valenciano de Investigaciones Agrarias' (IVIA). Respecto al cultivo de anteras en almendro, la formación de callos y producción de embriones se obtuvo mediante embriogénesis directa. Por otro lado, se ha conseguido regenerar por primera vez embriones a partir de microesporas aisladas en el cultivar de mandarino 'Mandarino Tardivo di Ciaculli'. Los resultados obtenidos muestran que la embriogénesis gamética y la regeneración de embriones homocigótos en almendro y mandarino, dos especies extremadamente recalcitrantes para la embriogenésis a partir de microesporas, es posible. Sin embargo, los resultados se ven afectados por muchos factores que necesitan estudios adicionales para comprender mejor el desarrollo embriogénico y para aumentar la tasa de obtención del embriones. Además, otra herramienta biotecnológica (manipulación de la ploidía) se aplicó con el objetivo de implementar el programa de mejora de níspero del IVIA. Las plantas poliploides en esta especie tienen un alto interés, pues podrían permitir la obtención de frutos sin semilla, por medio de la obtención directa de triploides o mediante cruzamiento entre tetraploides y diploides. Con el objetivo de obtener nuevos genotipos de níspero con diferentes niveles de ploidía (poliploides), se aplicó colchicina a semillas sin germinar con el fin de inducir la duplicación cromosómica y se obtuvieron 3 triploides (3x) y un tetraploide (4x). / La millora genètica té com objectiu la selecció de nous genotips amb millors característiques. Els mètodes de millora convencional basats en hibridacions i aquells basats en Biotecnologia (hibridació somàtica, transformació genètica, manipulació de la ploïdia, etc.) s'utilitzen per aconseguir nova variació genètica. La Biotecnologia proporciona eines poderoses en millora genètica, per exemple, l'obtenció d'haploides permet obtenir línies homozigòtiques en un sol pas, disminuint significativament el temps requerit usant mètodes convencionals. Pel que fa a espècies llenyoses, caracteritzades per autoincompatibilitat floral, llarg període juvenil i alt grau d'heterozigosi, aquesta tècnica és l'únic mètode d'obtenció de línies homozigòtiques. Els genotips haploides tenen un alt interès en estudis genòmics, sent utilitzats en estudis de mutacions, anàlisis genètics, mapatge genètic i transferència genètica. Aquest estudi té com objectiu la inducció d'embriogènesi gamètica en dos espècies mediterrànies molt importants: l'ametller (Prunus dulcis Mill.) a través del cultiu in vitro d'anteres i el mandariner (Citrus reticulata Blanco) per mitjà d'aïllament de micròspores. A més a més, s'ha estudiat l'obtenció de poliploides en nespra (Eriobotrya japonica (Thunb.) Lindl.) Amb l'objectiu d'aconseguir genotips amb diversos nivells de ploïdia. Els experiments es van dur a terme en els anys 2014, 2015 i 2016 a la 'Università degli Studi di Palermo' (UNIPA) i a 'l'Institut Valencià d'Investigacions Agràries' (IVIA). Respecte al cultiu d'anteres en ametller, la formació de calls i producció d'embrions es va obtenir mitjançant embriogènesi directa. D'altra banda, s'ha aconseguit per primera vegada la regeneració d'embrions a partir de micròspores aïllades en el conrear de mandariner 'Mandarino Tardivo di Ciaculli'. Els resultats obtinguts mostren que l'embriogènesi gamètica i la regeneració d'embrions homozigotics en ametller i mandariner, dues espècies extremadament recalcitrants per l'embriogènesi a partir de micròspores, és possible. No obstant això, els resultats es veuen afectats per molts factors que necessiten estudis addicionals per entendre millor el desenvolupament embriogènic i per augmentar la taxa d'obtenció dels embrions. A més, una altra eina biotecnològica (manipulació de la ploïdia) es va aplicar amb l'objectiu d'implementar el programa de millora de nespra de l'IVIA. Les plantes poliploides en aquesta espècie tenen un alt interès, ja que podrien permetre l'obtenció de fruits sense llavor, per mitjà de l'obtenció directa de triploides o mitjançant encreuament entre tetraploides i diploides. Amb l'objectiu d'aconseguir nous genotips de nespra amb diferents nivells de ploïdia (poliploides), es va aplicar colquicina a llavors sense germinar per tal d'induir la duplicació cromosòmica i es van obtenir 3 triploides (3x) i un tetraploide (4x). / Cimò, G. (2017). Ploidy manipulation for genetic improvement in some Mediterranean fruit crops [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/79874 / TESIS

No description available.

We propose an experimental model suitable for demonstrating allele frequency change in Drosophila melanogaster populations caused by selection against an easily scorable conditional lethal, namely recessive flightless alleles such as apterous and vestigial. Homozygotes for these alleles are excluded from reproduction because the food source used to establish each generation is accessible only by flight. The observed dynamics of flightless-allele frequencies generally follows the theoretically predicted pattern, with slight deviation toward less intense selection. We also suggest observing selection against flightindependent visible marker alleles in the same population as a meaningful comparison. The proposed experiments can easily be scheduled within one semester, and the expected data provide ample opportunities for discussion of quantitative evolutionary patterns.

No description available.

Endogamy levels are usually estimated using genealogical or molecular markers data. By means of both type of data from a traditional Brazilian tri-hybrid quilombo population aggregate (located at the Ribeira River Valley in the State of São Paulo), the aim of this work, using different methods, was to obtain reliable estimates of its average inbreeding coefficient, as well as to establish pertinent demographic inferences. The results we obtained are presented in three chapters. The first one, represented by the offprint of a published paper, deals with the estimation of the inbreeding coefficient using both a complete genealogical and comprehensive molecular information. F values were estimated for each community using all available pedigree information and averaging the inbreeding coefficients from all individuals represented in the genealogies. Molecular f values were estimated from the analysis of 30 highly heterogenous sets of molecular markers (14 biallelic SNPs and 16 multiallelic microsatellites), genotyped in different groups of individuals from the population. The second chapter (a research paper already published), presents a simplified method to estimate the variance of the inbreeding coefficient. The simple approximations we provided can be applied to a locus with any number of alleles, producing estimates fully validated by computer simulations. The last chapter is a manuscript yet to be published that deals with inbreeding and demographic inferences, obtained from the information of hundreds of thousands of biallelic SNP markers. A new manner to obtain estimates of Wright\'s fixation index f is presented, consisting in the use of the joint information of two sets of markers (one complete and another excluding markers in patent linkage disequilibrium). Quilombo demographic inferences were obtained by means of ROHs analyses, which were adapted to cope with a highly admixed population with a complex foundation history / Os níveis de endogamia de uma população são comumente estimados por meio do coeficiente de endocruzamento, que pode ser obtido de dados genealógicos (F) ou dados provenientes da análise de marcadores moleculares (f). O objetivo do trabalho foi obter estimativas confiáveis do coeficiente de endocruzamento populacional, bem como realizar inferências demográficas, usando dados de um agregado populacional quilombola miscigenado com ancestralidade complexa tri-híbrida, localizado no Vale do Rio Ribeira, na região sul do estado de São Paulo. No trabalho é apresentado em três capítulos. No primeiro (um trabalho já publicado), estimamos o coeficiente de endocruzamento usando dados genealógicos e moleculares. As estimativas genealógicas de F foram obtidas para cada comunidade por meio da média dos coeficientes individuais de todos os indivíduos representados nas genealogias da população. Os valores de f foram estimados por meio dos dados de 30 marcadores moleculares altamente heterogêneos (14 SNPs e 16 microssatélites), genotipados em diferentes grupos de indivíduos com diferentes finalidades. O segundo capítulo, representado por um trabalho também já publicado, apresenta um método simples para estimar a variância do coeficiente de endocruzamento f. As aproximações obtidas, validadas devidamente por simulações em computador, podem ser aplicadas a lóci multialélicos, produzindo estimativas que não diferem significativamente de outras aproximações complicadas descritas na literatura. O último capítulo (um manuscrito a ser submetido para publicação) apresenta inferências a respeito dos processos de endogamia e demografia no isolado quilombola, utilizando a informação de centenas de milhares de marcadores moleculares bialélicos. É apresentada uma nova maneira de se estimar o índice de fixação f de Wright, usando a informação combinada de dois conjuntos de marcadores (o conjunto completo de marcadores e um outro contendo apenas marcadores não ligados significativamente entre si). Também foram feitas inferências sobre a história demográfica do isolado por meio do estudo das regiões genômicas em homozigose (ROHs), uma contribuição inédita e importante do trabalho, adaptada à análise de um isolado populacional altamente miscigenado com contribuição tri-híbrida e uma história de fundação complexa