Varreduras genômicas para a detecção de variantes genéticas associadas à reprodução de cães
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Data
2018-10-25
Autores
Torrecilha, Rafaela Beatriz Pintor [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Variante funcional (functional variant - FV) é um polimorfismo da sequência de DNA que possui efeitos sobre a função ou mesmo sobre o nível de expressão de um ou mais genes. Por apresentarem alta probabilidade de interferência em fenótipos celulares, teciduais ou mesmo sistêmicos, as FVs são alvos frequentes de pressão de seleção negativa ou positiva em uma população. Algumas FVs podem, inclusive, causar perda parcial ou total da função gênica, caso no qual estas recebem a denominação de loss-of-function variant (LoFV). Os cães domésticos (Canis lupus familiaris) possuem baixa variabilidade genética decorrente da intensa seleção artificial feita pelo homem para fenótipos extremos de características morfológicas e comportamentais. Os altos níveis de endogamia nas populações caninas favorecem a intensificação da ação da deriva genética e, por consequência, o aumento da prevalência de FVs e LoFVs que seriam mantidas em baixa frequência se estas populações apresentassem maior variabilidade genética. Assim, o cão doméstico é um modelo valioso para estudos de processos fisiológicos e de doenças genéticas humanas. O recente surgimento de ferramentas para análise genômica têm auxiliado na identificação de FVs e LoFVs de interesse zootécnico e biomédico em cães. Estas variantes podem ser mapeadas através de duas estratégias distintas, porém complementares, de varredura genômica. A primeira, denominada de estudo de associação genômica ampla (Genome-Wide Association Study - GWAS), consiste no teste de associações entre genótipos e fenótipos. A segunda consiste na busca por combinações alélicas, chamadas de haplótipos, que ocorram em alta frequência, porém que apresentem deficiência de homozigose. No presente trabalho, utilizamos ambas as estratégias no mapeamento de FVs e LoFVs de alto impacto funcional associadas à reprodução de cães. No primeiro estudo, um GWAS para tamanho de ninhada foi conduzido em Cães Boiadeiros de Entlebuch, o qual revelou uma FV no gene do fator de crescimento e diferenciação 9 (growth/differentiation factor 9 – GDF9). No segundo estudo, reportamos haplótipos de alta frequência com deficiência de homozigotos nas raças Cão da Crista Chinesa, Cão Boiadeiro de Entlebuch, Labrador Retriever e Golden Retriever. Ambas as abordagens permitiram a identificação de variantes que podem estar associadas a prejuízos reprodutivos.
Functional variant (FV) is a DNA sequence polymorphism that has effects on the function or even the level of expression of one or more genes. FVs are frequent targets of negative or positive selection in a population due to its high probability of interfering in cell, tissue or system phenotypes. Some FVs may even cause partial or total loss of gene function, in which case they are called loss-of-function variants (LoFVs). Domestic dogs (Canis lupus familiaris) have low genetic variability resulting from intense human-driven artificial selection for extreme phenotypes of morphological and behavioral traits. High levels of inbreeding in canine populations favor the intensification of genetic drift and, consequently, an increase in the prevalence of FVs and LoFVs that would be maintained at low frequencies if these populations presented higher genetic variability. Thus, the domestic dog is a valuable model for studying physiological processes and human genetic diseases. The recent emergence of tools for genomic analysis has assisted in the identification of FVs and LoFVs of zootechnical and biomedical interest in dogs. These variants can be mapped through two distinct but complementary genomic scanning strategies. The first, known as Genome-Wide Association Study (GWAS), involves testing of phenotype-genotype associations. The second consists in the search for allelic combinations, called haplotypes, that occur in high frequency, but that present deficiency of homozygosity. In the present work, we used both strategies in the mapping of FVs and LoFVs of high functional impact associated with reproduction in dogs. In the first study, a GWAS for average litter size was conducted in Entlebucher Mountain dogs, which revealed a FV in the growth differentiation factor 9 gene (GDF9). In the second study, we reported high frequency haplotypes with deficiency of homozygosity in the Chinese Crested, Entlebucher Mountain, Labrador Retriever and Golden Retriever dog breeds. Both approaches allowed the identification of variants that may be associated with reproductive performance.
Functional variant (FV) is a DNA sequence polymorphism that has effects on the function or even the level of expression of one or more genes. FVs are frequent targets of negative or positive selection in a population due to its high probability of interfering in cell, tissue or system phenotypes. Some FVs may even cause partial or total loss of gene function, in which case they are called loss-of-function variants (LoFVs). Domestic dogs (Canis lupus familiaris) have low genetic variability resulting from intense human-driven artificial selection for extreme phenotypes of morphological and behavioral traits. High levels of inbreeding in canine populations favor the intensification of genetic drift and, consequently, an increase in the prevalence of FVs and LoFVs that would be maintained at low frequencies if these populations presented higher genetic variability. Thus, the domestic dog is a valuable model for studying physiological processes and human genetic diseases. The recent emergence of tools for genomic analysis has assisted in the identification of FVs and LoFVs of zootechnical and biomedical interest in dogs. These variants can be mapped through two distinct but complementary genomic scanning strategies. The first, known as Genome-Wide Association Study (GWAS), involves testing of phenotype-genotype associations. The second consists in the search for allelic combinations, called haplotypes, that occur in high frequency, but that present deficiency of homozygosity. In the present work, we used both strategies in the mapping of FVs and LoFVs of high functional impact associated with reproduction in dogs. In the first study, a GWAS for average litter size was conducted in Entlebucher Mountain dogs, which revealed a FV in the growth differentiation factor 9 gene (GDF9). In the second study, we reported high frequency haplotypes with deficiency of homozygosity in the Chinese Crested, Entlebucher Mountain, Labrador Retriever and Golden Retriever dog breeds. Both approaches allowed the identification of variants that may be associated with reproductive performance.
Descrição
Palavras-chave
Polimorfismo de sítio único (SNP), Haplótipo, Variante funcional, Reprodução, Canis lupus familiaris, Single nucleotides variants (SNV), Reproduction, Functional variant