CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A pesquisa foi realizada com o objetivo de avaliar geneticamente os zebuÃnos da raÃa Guzerà de corte do Nordeste brasileiro, nascidos entre 1976 e 2007, por meio do estudo da estrutura populacional, estimaÃÃo dos parÃmetros genÃticos aos 205(P205), 365(P365) e 550(P550) dias de idade e anÃlise do comportamento das linhas de tendÃncia genÃtica, fenotÃpica e de ambiente. O programa ENDOG foi utilizado para a anÃlise do pedigree e a estimaÃÃo dos parÃmetros baseados na probabilidade de origem do gene, tamanho efetivo (Ne), intervalo de geraÃÃes e coeficiente de endogamia. Os componentes de (co)variÃncia foram obtidos por meio da metodologia da MÃxima VerossimilhanÃa Restrita, utilizando o programa computacional MTDFREML. O modelo utilizado para P205 incluiu os efeitos aleatÃrios genÃticos, direto e materno, e de ambiente permanente, alÃm do efeito fixo de grupo de contemporÃneo. Para P365 e P550, foram considerados os mesmos efeitos fixos, porÃm, apenas o efeito genÃtico direto como efeito aleatÃrio. A estimativa das tendÃncias genÃtica, fenotÃpica e de ambiente para as caracterÃsticas foram obtidas pela regressÃo linear ponderada da mÃdia da variÃvel dependente (valores genÃticos, pesos observados e soluÃÃo dos GC) sobre o ano de nascimento. Os intervalos de geraÃÃes por passagem gamÃtica foram: 7,5Â4,5 (Pai-Filho), 7,9Â4,8 (Pai-Filha), 7,8Â4,2 (MÃe-Filho), 7,9Â3,9 anos (MÃe-Filha), com intervalo mÃdio de 7,9  4,4 anos. O tamanho efetivo sofreu um incremento entre os perÃodos 1976-78 a 1986-90 de 240% atingindo 674. Em seguida, houve uma reduÃÃo de 110% atingindo 318 em 1994, a partir do qual houve nova ascensÃo, chegando a 532 em 2006. O coeficiente de endogamia apresentou o maior crescimento da segunda para a sÃtima geraÃÃo, quando aumentou de 0,17% para 2,06%, contudo, a mÃdia de endogamia para animais endogÃmicos diminuiu de 15,66% para 6,75% durante o mesmo perÃodo. As herdabilidades diretas foram iguais a 0,11Â0,02(P205), 0,18Â0,02(P365) e 0,18Â0,02(P550). A herdabilidade materna para P205 foi igual a 0,01Â0,02. A tendÃncia genÃtica direta para P205, significativa (p<0,01) e igual a 0,0094 kg por ano, enquanto a tendÃncia genÃtica materna foi significativa (p<0,01) e igual a -0,0013 kg/ano. P365 e P550 apresentaram tendÃncias genÃticas direta altamente significativas (p<0,001) e iguais a 0,0214 kg/ano e 0,0255 kg/ano, respectivamente. As tendÃncias fenotÃpica e de ambiente foram altamente significativas (p<0,001) e respectivamente iguais a: 1,6584 e 1,6287(P205); 2,0829 e 2,0175 (P365); 3,3364 e 3,2237(P550) kg/ano. Existe baixa possibilidade de se selecionar os animais para o P205 devida a baixa herdabilidade, no entanto, P365 e P550 apresentaram herdabilidades moderadas, apresentando possibilidade de ganho. Os ganhos apesar de significativos devem ser atribuÃdos Ãs melhorias no ambiente. O tamanho efetivo à Ãtimo e a populaÃÃo nÃo apresenta riscos de extinÃÃo. Os intervalos de geraÃÃo foram altos, o que ocasionou perdas genÃticas, logo, a utilizaÃÃo de jovens touros avaliados por tempo limitado pode proporcionar reduÃÃo nos intervalos de geraÃÃo e consequentemente, aumento nos ganhos genÃticos / This research was carried out to assess genetically the breed Zebu Guzera beef cattle in Northeast of Brazil, borned between 1976 and 2007, through the estimation of genetic parameters for 205 (W205), 365 (W365) and 550 (W550) days of age, behavior analysis of the trend lines of genetic, phenotypic and environmental and interrelationship of population structure with genetic progress. The components of (co)variance were obtained by the method of restricted maximum likelihood using the computer program MTDFREML. The model used for the W205 include random genetic effects, direct and maternal, and permanent environment, beyond the fixed effect of contemporary group. For W365 and W550, they were considered fixed effects, however, only the direct genetic effect as random effect. The trend estimate genetic, phenotypic and environmental characteristics were obtained for the linear regression weighted average of the dependent variable (genetic values, weights and solution of the observed GC on the year of birth. The ENDOG program was used for the analysis of pedigree and parameters estimation based on the probability of gene origin, effective size (Ne), generation interval and coefficient of inbreeding. Direct heritability were estimated equal to 0.11  0.02 (W205), 0.18  0.02 (W365) and 0.18  0.02 (W550). The maternal heritability for W205 was to 0.01  0.02. The genetic trend for direct W205, significant (p<0.01) and equal to 0.0094 kg/year, while the maternal genetic trend was significant (p <0.01) and equal to -0.0013 kg/year. W365 and W550 showed highly significant direct genetic trends (p <0.001) and equal to 0.0214 kg/year and 0.0255 kg/year, respectively. The phenotypic and environmental trends were highly significant (p <0.001) and respectively: 1.6584 and 1.6287 (W205), 2.0829 and 2.0175 (W365), 3.3364 and 3.2237 (W550) kg/year. The intervals of generations: 7.5Â4.5 (Father-Son), 7.9Â3.9 (Father-Son), 7.8Â4.2 (Mother-Son), 7,9 Â4.8 (Mother-Daughter),with a mean interval of 7.9  4.4 years. The effective size has increased between the periods 1976-78 to 1986-90 from 240% to reach 674. Then there was a reduction of 110% reaching 318 in 1994, from which there was another rise, reaching 532 in 2006. The inbreeding coefficient showed the greatest growth from the second to the seventh generation, when increased from 0.17% to 2.06%, however, the average inbreeding in inbred animals decreased from 15.66% to 6.75% during the same period. There is low possibility to select the animals for the W205 due to low heritability, however, W365 and W550 showed moderate heritability, presenting opportunity for gain. The significantly gains should be attributed to improvements in the environment. The effective size is great and the population has no risk of extinction. The ranges of generation were high, which caused losses genetic. The use of young bulls evaluated for a limited time can provide reduction in the intervals of generation and increases in genetic gains

O presente estudo teve como objetivo avaliar a estrutura populacional, estimar parâmetros (coeficientes de herdabilidade e correlações) e determinar as tendências genéticas e fenotípicas de características de crescimento e adaptação em bovinos da raça Nelore, linhagem Lemgruber. O banco de dados utilizado nas análises constituiu-se de 39.290 animais no arquivo de pedigree e de 24.353 animais no arquivo de produção. Os parâmetros populacionais foram obtidos por meio dos softwares POPREP (GROENEVELD et al., 2009) e ENDOG v 3.2 (GUTIÉRREZ e GOYACHE, 2005). As estatísticas descritivas e os parâmetros genéticos para cada característica estudada foram estimadas por meio de quatro análises hepta-característica utilizando o programa VCE-6 (KOVAC & GROENEVELD, 2003) sob modelo animal completo. As tendências genéticas e fenotípicas foram obtidas pela regressão dos valores genéticos e fenotípicos respectivamente sobre o ano de nascimento dos animais e os coeficientes da regressão foram estimados por meio do método de quadrados mínimos. Apesar da endogamia média do rebanho ser considerada moderada verificou-se alta porcentagem de indivíduos endogâmicos e reduzido tamanho efetivo populacional. Além disso, o incremento contínuo de endogamia ao longo dos anos demonstra a necessidade de intervenção na seleção dos indivíduos para reprodução, de modo que, problemas futuros possam ser evitados. Os coeficientes de herdabilidade direta foram estimados em 0,24, 0,31, 0,31, 0,21, 0,19, 0,30, 0,41, 0,19 e 0,17 respectivamente para peso ao nascimento (PN), peso aos 120 dias de idade (P120), peso à desmama (PD), peso ao ano (PES12), ganho de peso pós desmama, de 205 aos 550 dias (GP345), ganho de peso na prova à pasto da ABCZ, em 224 dias (GP224), perímetro escrotal (PE), temperamento (TEMP), e repelência (REP) e indicam que a variabilidade genética aditiva existente é suficiente para a obtenção do ganho genético em resposta à seleção desde que sejam realizados ajustes, tanto nas estratégias de seleção adotadas para a obtenção de maiores ganhos nos valores genéticos, como também nos fatores ambientais que possam possibilitar ao máximo, a expressão do potencial genético dos animais. / The present study had as objective to evaluate the population structure, to estimate parameters (coefficients of heritability and correlation) and to determine the phenotypic and genetic trends for growth and adaptability traits in Nellore cattle, Lemgruber line. The database used in the analysis consisted of 39,290 animals in the pedigree and 24,353 animals in the production file. The population parameters were obtained from the software POPREP (Groeneveld et al., 2009) and ENDOG v 3.2 (Gutierrez and GOYACHE, 2005). The descriptive statistics and genetic parameters for each characteristic studied were estimated by four seven-traits analysis using the program VCE-6 (Kovac & GROENEVELD, 2003) which uses the animal model. The phenotypic and genetic trends were obtained by means of phenotypic and genetic values respectively on the year of birth of the animals and the regression coefficients were estimated by the method of least squares. Although the average inbreeding of the herd being considered moderate, there was high percentage of inbred individuals and small effective population size. Furthermore, the continuous increase in inbreeding over the years demonstrates the need for intervention in the selection of individuals for reproduction, so that future problems can be avoided. Direct heritability coefficients were estimated as 0.24, 0.31, 0.31, 0.21, 0.19, 0.30, 0.41, 0.19 and 0.17 respectively for birth weight (PN), weight 120 days of age (P120), weaning weight (PD), weight at 12 months of age (PES12), weight gain after weaning from 205 to 550 days (GP345), weight gain during the pasture test of ABCZ in 224 days (GP224), scrotal circumference (PE), docility (TEMP) and repellency (REP) and indicate that the additive genetic variability is sufficient to obtain genetic gain in response to selection as far as adjustments in selection strategies are adopted to achieve larger gains in breeding values, and environmental factors that may allow the expression of the genetic potential of the animals.

O objetivo deste trabalho foi analisar a estrutura genética populacional e os efeitos do programa de melhoramento genético em um rebanho Nelore comercial, que visa a venda de reprodutores avaliados geneticamente. O banco de dados era composto pelos registros de produção de 417.552 animais, nascidos entre 1984 e 2007, e o de pedigree de 483.748 animais. Com o intuito de estudar a estrutura populacional, foram utilizados os softwares ENDOG v. 4.6 e POPREPORT para se calcular o coeficiente de endogamia (F), o coeficiente médio de parentesco individual (AR), numero efetivo de ancestrais e de fundadores, numero de ancestrais que contribuem com 50% da variabilidade genética da população e intervalo de gerações. O coeficiente de endogamia calculado para a população em estudo foi igual a 0,12% e o AR a 0,18%. Os números efetivos de ancestrais (fa) e de fundadores (fe) foram iguais a 64 e 147, respectivamente. Para a população estudada, 70 indivíduos explicam sua variabilidade genética. O intervalo de geração calculado para os quatro passos gaméticos pai-filho, pai-filha, mãe-filho, mãe-filha foram de 9,26, 7,30, 9,29 e 5,83 anos, respectivamente, quando se considera somente as progênies que se tornaram reprodutores no programa de melhoramento, e de 7,45, 7,40, 6,02, 5,93 anos, respectivamente, quando se considera todas as progênies nascidas. O progresso genético esperado para as características peso a desmama (PD), ganho de peso da desmama ao sobreano (GP345), perímetro escrotal (PE) e musculatura era de 1,10 kg/ano, 1,05 kg/ano, 0,28 cm/ano e 0,04 un/ano, respectivamente. Entretanto, o progresso genético observado para as mesmas características foram iguais a 0,51 kg/ano, 1,03 kg/ano, 0,11 cm/ano e 0,03 un/ano, respectivamente. / The objective of the present research was to analyze the population genetic structure and the effects of breeding program in a Nellore commercial herd, aimed at the sale of breeders genetically evaluated. The database was composed by production records by 417552 animals, born between 1984 and 2007, and the pedigree records by 483748. For describe the population structure, to ENDOG v. 4.6 and POPREPORT were used to calculate inbreeding coefficient (F), average relatedness coefficients (AR), effective number of ancestors and founders, number of ancestors that contribute with 50% of genetic variability of population and generation intervals. The inbreeding coefficient calculated to the population in study is 0.12% and AR is 0.18%. The effective number of ancestors (fa) and founders (fe) was 64 and 147, respectively. For the population in study, 70 individuals explain 50% of genetic variability. The generation\'s intervals for the four paths genetic, sire-son, siredaughter, dam-son, dam-daughter, was 9,26, 7,30, 9,29 e 5,83 years, respectively, when considered only progenies kept reproduction, and was 7,45, 7,40, 6,02, 5,93 years, respectively, when all born progenies are considered. The genetic progress waited to the characteristics weaning weight (WW), weight gain from weaning to 18 months (WG345), scrotal circumference (CE) and muscle were 1.10 kg.year-1, 1.05 kg.year-1, 0.28 cm.year-1 and 0.04 unit.year-1, respectively. However, the genetic progress observed to the same characteristics was 0.51 kg.year-1, 1.03 kg.year-1, 0.11 cm.year-1 and 0.03 unit.year-1, respectively.

O bioma Mata Atlântica tem sofrido com a fragmentação florestal e como forma de reestabelecer ambientes florestais são realizados plantios de restauração. Porém, por muito tempo houve preocupação somente com a composição florística das áreas e a diversidade genética foi negligenciada. Além disso, muitas áreas são implantadas a partir de sementes coletadas em áreas florestais geralmente pouco conservadas, pequenas e isoladas, o que pode comprometer a qualidade genética das mudas, produzindo indivíduos menos adaptados em decorrência da depressão endogâmica. Assim este trabalho teve como objetivo principal analisar o aspecto genético em áreas de restauração na região do Pontal do Paranapanema e área natural de referência, o Parque Estadual Morro do Diabo (PEMD), utilizando o jatobá (Hymenaea courbaril L.) como espécie modelo. No capítulo 1 com o objetivo de verificar a diversidade genética de H. courbaril em áreas de restauração florestal, foram selecionadas duas áreas de plantio com espécies nativas. Nestas áreas e no PEMD foram coletadas amostras foliares de indivíduos adultos que foram genotipadas para oito locos microssatélites. No PEMD ainda foram coletados frutos em 12 matrizes para caracterização do sistema reprodutivo. As três áreas estudadas apresentaram diversidade genética e níveis de endogamia similares. Nas três áreas de estudo foi identificada baixa estruturação genética espacial. Houve predomínio de fecundação cruzada para a produção de frutos na área natural, porém a taxa de cruzamentos entre indivíduos aparentados foi até dez vezes maior que a observada em outras populações da espécie. No capítulo 2 com o objetivo de verificar se há depressão endogâmica em progênies provenientes do PEMD foram selecionadas 320 sementes de 12 matrizes. Estas e seus frutos foram medidos. As plântulas a que deram origem também foram mensuradas, mensalmente, durante 15 meses. Todos os indivíduos foram genotipadas para oito locos microssatélites. A coancestria, foi estimada e os indivíduos separados em: não aparentados (tu), aparentados (tr) e autofecundação (s). Foi verificada diferença entre as métricas das plantas de acordo com o nível de coancestria entre indivíduos. Também foram estimados os valores de depressão endogâmica (ID). A quantidade de indivíduos irmãos de autofecundação foi muito pequena, sendo a maioria proveniente de cruzamento entre indivíduos não aparentados. A depressão endogâmica por autofecundação foi mais evidente no peso e tamanho dos frutos, e amena ou inexistente para os demais caracteres. Isto provavelmente por estas sementes terem sido coletadas em um fragmento grande e bem conservado e que ainda não sofre as consequências da depressão endogâmica. Assim, nosso trabalho mostrou que áreas de restauração florestal que seguiram as recomendações genéticas de implantação, apresentam diversidade genética suficiente para H. courbaril, podendo estas áreas serem fonte de coleta de sementes no futuro. E que os indivíduos provenientes de sementes do PEMD não apresentaram efeito de depressão endogâmica até 15 meses de desenvolvimento em viveiro. / The Brazilian Atlantic Forest was severely deforested and restoration initiatives are necessary to reestablish environments. However, for a long time there is only concern over floristic composition and the genetic diversity has been neglected. In addition, several restoration areas are planted from seeds collected in forest areas that are generally poorly preserved, small and isolated, which may compromise the genetic quality of the seedlings, producing less adapted individuals due to inbreeding depression. The aim of this work was to analyze the genetic aspects of Hymenaea courbaril L. in restoration areas in Pontal do Paranapanema region, and a natural reference forest, the Morro do Diabo State Park (PEMD), where seeds were also collected. In Chapter 1, to verify the genetic diversity of H. courbaril in areas of forest restoration, using eight microsatellites, two restoration areas were selected. In these areas and in the PEMD, leaf samples from adult individuals were collected. In the PEMD, fruits were collected in 12 seed trees for mating system characterization. The three areas presented similar genetic diversity and levels of inbreeding. Low spatial genetic structure was identified in the three studied areas. In the natural forest, fruits were mainly produced through outcrossings, but the rate of mating among relatives was up to ten times higher than the observed in other H. courbaril populations. In Chapter 2, to verify the inbreeding depression in the PEMD were selected 320 seeds from eight seed trees. The seeeds and their fruits were measured. The seedlings were also measured monthly, during 15 months. All seedlings were genotyped with eight microsatellite loci. From the pairwise coancestry the seedlings were separated into three categories: outcrossing among unrelated individuals (tu), outcrossing among related individuals (tr), and selfing (s). We verified differences among groups in the metrics of seedlings according to the level of coancestry among individuals. The values of inbreeding depression (ID) were also estimated. The number of selfed seedlings were very small, and the majority were from outcrossing among unrelated individuals. Inbreeding depression by selfing was more evident in weight and size fruit, and was insignificant or non-existent for other characters. This is probably because these seeds were collected in a large and preserved forest fragment, that does not suffer the consequences of inbreeding depression yet. Thus, our work showed that forest restoration areas that followed the genetic recommendations present enough genetic diversity for H. courbaril, and these areas may be a source of seeds for collection in the future. Besides that, seedlings from seed trees in PEMD did not present inbreeding depression effect up to 15 months of nursery development.

Os objetivos do presente trabalho se dirigem ao estudo da variabilidade genética e da depressão por endogamia em sete populações de milho de ampla base genética, visando ao melhoramento de populações e obtenção de linhagens endogâmicas promissoras. Foram instalados onze experimentos em blocos casualizados em um local (Anhembi, SP), com diferentes conjuntos (N) de progênies S1 obtidos de sete populações (GO-D: dentado, GO-F: flint, GO-L: espiga longa, GO-G: espiga grossa; e compostos G3, G4 e GO-S). Foram estimadas a variância genética entre médias de progênies (2G), a variância fenotípica entre médias de progênies?^ (2F?^) e o coeficiente de herdabilidade (sentido amplo) para médias de progênies (2X). As estimativas de h 2Xhforam altas para peso de espigas (PE: 0,89 a 0,94), comprimento da espiga (CE: 0,77 a 0,88) e diâmtero da espiga (DE: 0,77 a 0,92); e menores para altura da planta (AP: 0,58 a 0,80) e altura da espiga (AE: 0,54 a 0,84), demonstrando alto potencial das populações para seleção recorrente com progênies S1. A variável PE nas populações base usadas como testemunha, mostrou valores variando de 11200 kg.ha-1 (GO-D) a 12800 kg.ha-1 (G3). As médias de progênies S1 entre populações variaram de 6070 kg.ha-1 (GO-F) a 7380 kg.ha-1 (G4); a depressão por endogamia nas progênies S1 variou de 37,5% (G4) a 48,0% (G3) em relação à população base. Os estudos sobre endogamia envolvendo as sete populações foram conduzidos com amostras da população original não endógama (S0) e das gerações S1 e S2 de autofecundação. Os experimentos foram conduzidos em Londrina (PR) e Piracicaba (SP) em blocos casualizados com parcelas subdivididas, com as populações representadas nas parcelas e as gerações de endogamia nas sub-parcelas. A estimação da depressão por endogamia foi obtida pelo modelo de regressão linear Y = µ0 + ?, sendo ? a depressão por endogamia para 100% de homozigose. A depressão esperada para 50% de homozigose é ?/2, cujo valor em percentagem variou de 25,4% a 41,4% em Piracicaba e de 23,1% a 39,3% em Londrina. Para os demais caracteres, os efeitos depressivos foram menores, geralmente <25% para AP e AE e <15% para DE e CE. / The objectives of the present work were directed for the study of genetic variability and inbreeding depression in seven maize populations of broad genetic base, as a guide for population improvement and development of promising inbred lines. The field evaluation was in eleven experiments (randomized complete blocks) in one location (Anhembi, SP) with different groups (N) of S1 progenies obtained of seven populations (GO-D: dent type, GO-F: flint type, GO-L: long ear, GO-G: thick ear; and composites G3, G4 e GO-S). Estimates were obtained for genetic variance (?^: progeny mean basis), phenotypic variance of progeny means (2G2F?^), and coefficient of heritability (broad sense) for progeny means (2Xh). Estimates of 2Xhwere high for ear weight (PE: 0.89 to 0.94), ear length (CE: 0.77 to 0.88) and ear diameter (DE: 0.77 to 0.92); and lower for plant height (AP: 0.58 to 0.80) and ear height (AE: 0.54 to 0.84), thus showing the high potential of the populations for recurrent selection based on S1 progenies. Ear yield (PE) in the base populations used as ckecks varied from 11200 kg.ha-1 (GO-D) to 12800 kg.ha-1 (G3). The means of S1 progenies varied from 6070 kg.ha-1 (GO-F) to 7380 kg.ha-1 (G4); the inbreeding depression in S1 progenies varied from 37.5% (G4) to 48.0% (G3) relative to the non-inbred population. For the studies on inbreeding in the seven populations samples of the original non-inbred populations (S0) and S1 and S2 generations of inbreeding were used. Filed experiments were carried out in Londrina (PR) and Piracicaba (SP) in randomized blocks with spli-plots, where populations were in the whole plots and inbreeding generations in the sub-plots. The estimates of inbreeding depression were obtained by the linear regression model Y = µ0 + ?, where ? is the iinbreeding depression for 100% homozygosity. The expected inbreeding depression for 50% homozygosity is ?/2, and the estimates in percentage varied from 25.4% to 41.4% in Piracicaba and from 23.1% to 39.3% in Londrina. For the other traits the inbreeding effects were lower, in general <25% for AP and AE and <15% for DE and CE.

Les Troubles du Spectre Autistique (TSA) forment un groupe hétérogène de troubles neurodéveloppementaux caractérisés par des déficits de l’interaction sociale et de la communication ainsi que la présence de comportements répétitifs et d’intérêts restreints. Les TSA affectent environ un individu sur 68. Ils se manifestent généralement durant les trois premières années de vie mais, pour certains cas, les symptômes sont reconnus plus tard, quand les exigences sociales augmentent. Les études de jumeaux et la récurrence des troubles dans certaines familles démontrent l’importance des facteurs génétiques dans la vulnérabilité aux TSA. Cependant, l’architecture génétique des TSA reste difficile à caractériser car elle est extrêmement hétérogène et il est très compliqué d’identifier, pour chacun des patients, la combinaison d’allèles à risque. Notre laboratoire a identifié la première voie génétique associée aux TSA – la voie NLGN-NRXN-SHANK- qui joue un rôle clé dans la plasticité synaptique. Il existe un nombre de plus en plus grand de gènes associés aux TSA mais peu d’études ont été réalisées sur des cohortes épidémiologiques et dans des populations isolées. L'analyse des données de génotypage et de séquençage d’exome de 357 individus issus des îles Féroé (36 patients, 136 apparentés des patients, 185 témoins) nous a permis de mettre en évidence un nombre plus important de Variations du Nombre de Copies (CNVs), un coefficient de consanguinité supérieur, un plus grand nombre de mutations homozygotes et délétères ainsi qu’un Polygenic Risk Score (ASD-PRS) supérieur chez les patients TSA comparés aux individus témoins. Notre analyse confirme le rôle de plusieurs loci associés aux TSA (NRXN1, ADNP, délétion 22q11) et a permis d’identifier de nouvelles mutations tronquant la protéine (GRIK2, ROBO1, NINL et IMMP2L) ou récessives (KIRREL3 et CNTNAP2) affectant des gènes déjà associés aux TSA. Nous avons également mis en évidence trois nouveaux gènes candidats jouant un rôle important dans la plasticité synaptique (RIMS4, KALRN et PLA2G4A) à travers la présence de mutations de novo délétères chez des patients sans déficience intellectuelle. Au total, nous avons pu identifier une cause génétique expliquant les TSA pour 11% des patients et au moins une mutation fortement délétère dans des gènes candidats chez 39% des patients. Aucune cause génétique n'a pu être trouvée chez 50% des patients. En résumé, notre étude permet de mieux comprendre l’architecture génétique des TSA dans les populations isolées en soulignant à la fois l'impact des variants communs et des variants rares mais également en révélant le rôle de nouveaux gènes pour les TSA. Ces gènes codent pour des protéines essentielles pour le neurodéveloppement et l’identification de ces facteurs impliqués dans la formation et l'entretien des synapses pourrait ainsi fournir de nouvelles pistes afin de mieux comprendre les bases biologiques des TSA et de découvrir de nouvelles stratégies thérapeutiques. Il est cependant nécessaire de comprendre plus avant l'impact de la combinaison de différentes mutations sur la fonction neuronale afin de mieux caractériser l’architecture génétique des TSA. / Autism Spectrum Disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as the presence of repetitive behaviors and restricted interests. ASD affects approximately one in 68 individuals. They usually occur during the first three years of life but, in some cases, symptoms are recognized later, when social demands increase. There is a strong genetic component to ASD, as indicated by the recurrence risk in families and twin studies. However, the genetic architecture of ASD remains largely unknown because of its extreme heterogeneity. It is very challenging to identify, for each patient, the combination of risk alleles. Our laboratory identified the first genetic pathway associated with ASD – the NLGN-NRXN-SHANK pathway – playing a key role in synaptogenesis during development. There are an increasing number of genes associated with ASDs but few studies have been conducted on epidemiological cohorts and isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 patients with ASD, 136 of their relatives and 185 non-ASD controls. Data from SNP array and whole exome sequencing revealed that patients had a higher burden of copy-number variants, higher inbreeding status, higher load of homozygous deleterious mutations, and a higher ASD polygenic risk score compared to controls. We confirmed the role of several ASD-associated loci (NRXN1, ADNP, 22q11 deletion) and identified new truncating (GRIK2, ROBO1, NINL and IMMP2L) or recessive variants (KIRREL3 and CNTNAP2) affecting genes already associated with ASD. We have also identified three novel candidate genes playing key roles in synaptic plasticity (RIMS4, KALRN and PLA2G4A) carrying deleterious de novo mutations in patients without intellectual disability. Overall, for 11% of individuals with ASD, a known genetic cause was identified, for 39% at least one strongly deleterious mutation was identified in a compelling candidate gene and for 50% no obvious genetic cause was detected. In summary, our study provides a better understanding of the genetic architecture of ASD in isolated populations by highlighting both the impact of common and rare variants but also by revealing the role of new genes for ASD. These genes code for proteins that are essential for neurodevelopment. The identification of these factors involved in synapse formation and maintenance could provide new leads to better understand the biological basis of ASD and find novel therapeutic strategies. However, it is necessary to further understand the combined impact of different mutations on neuronal function in order to better characterize the genetic architecture of ASD.

La consanguinité et l’hybridation sont deux processus génétiques pouvant avoir des effets antagonistes dans les élevages d’auxiliaires de lutte biologique. L’hybridation peut minimiser les risques de dépression de consanguinité (diminution de fitness des individus consanguins), et favoriser l’apparition de phénotypes avantageux. Bien que les mécanismes de la dépression de consanguinité et des conséquences de l’hybridation soient bien connus, très peu d’études ont été réalisées dans le cadre de la lutte biologique. Il convient d’évaluer les effets réels de la consanguinité et de l’hybridation sur la fitness des auxiliaires pour orienter les pratiques de l’industrie de la lutte biologique. Dans le cadre d’une collaboration public-privé, des données ont été produites sur les effets de la consanguinité chez les quatre auxiliaires Allotropa burrelli, Chrysoperla near comanche, Cryptolaemus montrouzieri et Macrolophus pygmaeus. La consanguinité a notamment provoqué une baisse de 30% du succès reproducteur chez M. pygmaeus. Une étude approfondie des conséquences de l’hybridation intra-spécifique a alors été réalisée en utilisant quatre populations de M. pygmaeus. Trois groupes génétiques séparés par un fort isolement reproducteur ont été mis en évidence. Néanmoins, un avantage de fitness pour les individus issus de croisements entre parents génétiquement distants a été mis en évidence au sein de chaque groupe génétique. Ce travail de thèse apporte des données utilisables à court-terme par les entreprises partenaires. Il contribue par ailleurs à créer un corpus de données pour mieux évaluer l’importance réelle des effets génétiques dans les élevages d’auxiliaires. / Inbreeding and hybridization are two genetic processes that may have antagonistic effects in biological control agents (BCAs) rearing. Hybridization can minimize the risk of inbreeding depression (decrease in fitness of inbred individuals), and favor the emergence of advantageous phenotypes. Although the mechanisms of inbreeding depression and the consequences of hybridization are well known, very few studies have been carried out in the context of biological control. The actual effects of inbreeding and hybridization on the fitness of BCAs should be assessed to guide the practices of the biocontrol industry. In a public-private collaboration, data were generated on the effects of inbreeding in the four BCAs Allotropa burrelli, Chrysoperla near comanche, Cryptolaemus montrouzieri and Macrolophus pygmaeus. Inbreeding resulted in a 30% decrease in reproductive success in M. pygmaeus. A thorough study of the consequences of intra-specific hybridization was then carried out using four populations of M. pygmaeus. Three genetic groups separated by strong reproductive isolation were identified. Nevertheless, a fitness advantage for individuals from crosses between genetically distant parents has been highlighted within each genetic group. This work brings data usable in the short term by the partner companies. It also helps to create a corpus of data to better evaluate the real importance of genetic effects in BCAs rearing.

Le cadre général de cette thèse est la question de la relation génotype-phénotype, abordée à travers l'analyse du phénomène d'hétérosis chez la levure, dans une approche associant biologie, mathématiques et statistiques. Antérieurement à ce travail, un très gros jeu de données hétérogènes, correspondant à différents niveaux d'organisation (protéomique, caractères de fermentation et traits d'histoire de vie), avait été recueilli sur un dispositif demi-diallèle entre 11 souches appartenant à deux espèces. Ce type de données est idéalement adapté pour la modélisation multi-échelle et pour tester des modèles de prédiction de la variation de phénotypes intégrés à partir de caractères protéiques et métaboliques (flux), tout en tenant compte des structures de dépendance entre variables et entre observations. J’ai d'abord décomposé, pour chaque caractère, la variance génétique totale en variances des effets additifs, de consanguinité et d'hétérosis, et j’ai montré que la distribution de ces composantes permettait de définir des groupes bien tranchés de protéines dans lesquels se plaçaient la plupart des caractères de fermentation et de traits d'histoire de vie. Au sein de ces groupes, les corrélations entre les variances des effets d'hétérosis et de consanguinité pouvaient être positives, négatives ou nulles, ce qui a constitué la première mise en évidence expérimentale d’un découplage possible entre les deux phénomènes. Le second volet de la thèse a consisté à interfacer les données de protéomique quantitative avec un modèle stœchiométrique du métabolisme carboné central de la levure, en utilisant une approche de modélisation à base de contraintes. M'appuyant sur un algorithme récent, j’ai cherché, dans l'espace des solutions possibles, celle qui minimisait la distance entre le vecteur de flux et le vecteur des abondances observées des protéines. J’ai ainsi pu prédire un ensemble de flux et comparer les patrons de corrélations entre caractères à plusieurs niveaux d'intégration. Les données révèlent deux grandes familles de caractères de fermentation ou de traits d'histoire de vie dont l'interprétation biochimique est cohérente en termes de trade-off, et qui n'avaient pas été mises en évidence à partir des seules données de protéomique quantitative. L'ensemble de mes travaux permet de mieux comprendre l'évolution de la relation entre génotype et phénotype. / The general framework of this thesis is the issue of the genotype-phenotype relationship, through the analysis of the heterosis phenomenon in yeast, in an approach combining biology, mathematics and statistics. Prior to this work, a very large set of heterogeneous data, corresponding to different levels of organization (proteomics, fermentation and life history traits), had been collected on a semi-diallel design involving 11 strains belonging to two species. This type of data is ideally suited for multi-scale modelling and for testing models for predicting the variation of integrated phenotypes from protein and metabolic (flux) traits, taking into account dependence patterns between variables and between observations. I first decomposed, for each trait, the total genetic variance into variances of additive, inbreeding and heterosis effects, and showed that the distribution of these components made it possible to define well-defined groups of proteins in which most of the characters of fermentation and life history traits took place. Within these groups, the correlations between the variances of heterosis and inbreeding effects could be positive, negative or null, which was the first experimental demonstration of a possible decoupling between the two phenomena. The second part of the thesis consisted of interfacing quantitative proteomic data with the yeast genome-scale metabolic model using a constraint-based modelling approach. Using a recent algorithm, I looked, in the space of possible solutions, for the one that minimized the distance between the flux vector and the vector of the observed abundances of proteins. I was able to predict unobserved fluxes, and to compare correlation patterns at different integration levels. Data allowed to distinguish between two major types of fermentation or life history traits whose biochemical interpretation is consistent in terms of trade-off, and which had not been highlighted from quantitative proteomic data alone. Altogether, my thesis work allows a better understanding of the evolution of the genotype-phenotype map.

Translocations are an important aspect of the management of natural populations in an increasingly fragmented landscape. Maintaining connectivity and gene flow is beneficial for both contemporary fitness and adaptive potential in the face of environmental change. Genetic rescue (GR) can alleviate inbreeding depression, genetic load, and increase adaptive potential of populations. Here, I have translocated 10 (5 of each sex) brook trout (Salvelinus fontinalis) to four geographically proximate and environmentally similar fragmented stream-dwelling populations of brook trout in Virginia to test for genetic rescue. The translocated brook trout contributed to more families than would be expected under neutral introgression, and hybridization resulted consistently in larger full-sibling family sizes. In the cohort immediately following translocation I observed relatively high (>20%) introgression in 3 of the 4 recipient sites, and in one recipient population 57.7 % of the offspring had at least one migrant parent. During the post-translocation period favorable regional climatic conditions resulted in large cohorts across recipient sites and controls, however the percent increase in juvenile abundance scales to initial genetic diversity and patch size. I observe strong evidence of hybrid vigor through consistently larger body sizes of hybrid offspring. At this point I cannot rule out potential negative effects of translocations such as outbreeding depression with out sampling more cohorts following genetic recombination. However, I provide an empirical and replicated foundation to begin assessing the efficacy of GR-motivated translocations for headwater fish conservation, and make a substantial contribution to the growing body of GR-literature.

White-tailed deer (Odocoileus virginianus) have been intensively studied across their range. However, many aspects of the white-tailed deer’s ecology have not been studied or are difficult to study. The advent of global positioning system (GPS) collar technology and molecular genetics techniques now allows researchers to collect fine-scale and cryptic phenomena. In addition, selective harvest of male white-tailed deer, based on antler size, has not been critically evaluated. Thus, development and use of quantitative genetics models will be useful for elucidating the effects of selective harvest on mean population antler size. I used GPS collar technology to further understand white-tailed deer movement ecology. First, I determined the efficacy and influence of a high-tensile electric fence (HTEF) on deer movements. The HTEF controlled deer movements when properly maintained and had little influence on deer spatial dynamics, making it a safe and cost-effective alternative to traditional fencing. Second, I studied fine-scale deer movements using GPS collars collecting locations every 15 minutes. Hourly deer movements were greatest in the morning and evening. Parturition and rut influenced movements of females and males, respectively whereas weather and moon phase had minimal influence on movements. Molecular genetics techniques are becoming more widespread and accessible, which may allow insight into the link between genetics and antler size. I found deer in 3 diverse populations from Mississippi, Oklahoma and Texas were relatively heterozygous and unrelated. Groups of deer with similar antler characteristics did not appear to be inbred or share common ancestors. In addition, there was not a strong link between individual multi-locus heterozygosity and antler points or score. Selective harvest has been implicated in causing negative evolutionary and biological responses in several ungulate species. To better determine how selective harvest (i.e., culling; the removal of deer with inferior antlers) affects white-tailed deer antler size, I used quantitative genetic models to simulate response of deer antlers to selection. In simulated controlled breeding situations response to selection was rapid, resulting in improvement in antler size. In simulated free-ranging populations response of antler size to selection was slow and only resulted in minimal increases in antler points after 20 years.