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Comparative genomics of indels in primate lineages and the possible effect of the MET promoter indel on gene expression

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Abstract
Approximately six million years ago, the human and chimpanzee lineages diverged from a common ancestor resulting in two distinct species with a great number of different morphological, behavioral, cognitive and other phenotypic traits. However, their genomes are more than 98.5% identical at protein-coding loci, and genomic differences between these two species hover around 2.4%, excluding repeats and low complexity DNA and including insertions and deletions (indels). It is believed that most of the genetic foundation for the differences among these two lineages lies at the level of gene regulation. Our work focused on lineagespecific large (> 10 bp) indels located in promoter regions that may affect gene expression and protein product levels. Our goal was to validate indels, in order to differentiate real features from computational artifacts. We started by identifying 64 indels, through the alignment of orthologous regions of human, chimpanzee, gorilla, orangutan and macaque (in-silico analysis), located at the 5’ side of the gene and at distance no more than 2 kb away from its nearest gene transcription start site. To validate the indels, PCR and electrophoresis (in-vitro) analysis was performed with all of them. We found two distinct indels, which were unique to the human lineage, in genes associated with neurodevelopment and the female-sexual development, MET and DMRTA2. Since previous studies suggest that most of the differences that exist between humans and chimpanzees are in areas related to the cognitive ability and fertility, our results could indicate that the derived variants observed in the human lineage might be important for processes that make the humans distinct to the other hominids. Moreover, given that most of the divergences that exist between humans and chimpanzees are due to differential gene expression, the promoters described herein could serve as models for in-vitro gene expression assays for evaluating how these fixed indels may affect gene expression in both species.
Hace aproximadamente 6 millones de años, el linaje de los humanos y el chimpancĂ© divergieron de un ancestro en comĂºn, resultando en dos distintas especies con una gran cantidad de diferencias a nivel morfolĂ³gico, cognitivo y de comportamiento, entre otras caracterĂ­sticas fenotĂ­picas. Sin embargo, sus genomas son mĂ¡s de un 98.5% idĂ©nticos en loci codificantes para proteĂ­nas, y las diferencias genĂ³micas entre ambas especies son el 2.4%, excluyendo regiones repetitivas y de baja complejidad, e incluyendo inserciones y deleciones (indels). Por lo tanto, se cree que la base genĂ©tica para las diferencias observadas entre ambas especies subyace a nivel de regulaciĂ³n gĂ©nica. Nuestro trabajo se enfocĂ³ en indels (>10 bp) localizados en regiones promotoras que pueden afectar la expresiĂ³n de los genes y la cantidad de productos proteicos. Nuestra meta fue validar la presencia de indels, para asĂ­ diferenciar entre artefactos computacionales o indels reales. Se comenzĂ³ identificando 64 indels, a travĂ©s de alineamientos de secuencias de ADN de regiones ortĂ³logas en humanos, chimpancĂ©, gorila, orangutĂ¡n y macaco (anĂ¡lisis in-silico), localizados en el lado 5’ a una distancia de no mĂ¡s de 2 kilo bases del comienzo del sitio de transcripciĂ³n mĂ¡s cercano. Se llevĂ³ a cabo la validaciĂ³n de los indels a travĂ©s de su amplificaciĂ³n mediante PCR y electroforesis (anĂ¡lisis in-vitro). Se encontraron dos indels que eran Ăºnicos para el linaje de los humanos, ambos en genes asociados al desarrollo cognitivo y desarrollo sexual femenino, MET y DMRTA2. Dado que estudios previos sugieren que la mayorĂ­a de las diferencias fenotĂ­picas que existen entre el humano y el chimpancĂ© se observan en Ă¡reas relacionadas a la habilidad cognitiva y la fertilidad, nuestros resultados podrĂ­an indicar que las variantes derivadas observadas en el linaje de los humanos es importante para aquellos procesos que hacen a los humanos distintos de los otros homĂ­nidos. En adiciĂ³n, puesto que la mayorĂ­a de las divergencias que existe entre el humanos y el chimpancĂ© se debe a expresiĂ³n gĂ©nica diferencial, los promotores previamente descritos podrĂ­an servir como modelos para ensayos de expresiĂ³n in-vitro, para evaluar cĂ³mo estos indels fijados podrĂ­an afectar la expresiĂ³n de los genes en ambas especies.
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Date
2016
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Research Projects
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Keywords
Human and chimpanzee lineages, Human genome, Chimpanzee genome
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