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Integrative functional genomic analyses identify novel genetic variants influencing skin pigmentation in indigenous Africans [RNA-seq]

ABSTRACT: Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. We identified 1,157 candidate variants influencing skin pigmentation in indigenous Africans by genome-wide association studies and scans of natural selection based on differentiation in allele frequencies between lightly pigmented southern African Khoesan populations and other darkly pigmented African populations. We applied massively parallel reporter and chromosome conformation capture assays to identify novel regulatory variants and their target genes related to skin pigmentation in melanocytic cells. We identified 165 SNPs showing strong differential regulatory activities between alleles. Combining CRISPR-mediated genome editing, transcriptome profiling and melanin assays, we identified causal regulatory variants impacting pigmentation near MFSD12/HMG20B, MITF, OCA2, and DDB1/CYB561A3/TMEM138. We identified CYB561A3 as a novel gene regulating pigmentation by impacting genes involved in oxidative phosphorylation and melanogenesis. Our results broaden our understanding of the genetic basis of human skin color diversity and human adaptation. To test the role of candidate enhancers and variants in skin pigmentation, we performed CRISPR inhibition or knockout of enhancers containing the functional variants identified by MPRA in melanocytic cells. Then, we performed gene expression profiling analysis using data obtained from RNA-seq of these CRISPR-edited cells. We also performed RNA-seq using CYB561A3-koncout MNT1 cells or CYB561A3-overexpressing MNT1 cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE213142 | GEO | 2022/09/15

REPOSITORIES: GEO

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Project description:Ma-Huang chicken as a high-quality broiler is one of the most popular chickens in the frozen chicken market. However, some chicken may instead have white or lighter skin, which directly causes economic losses every year. To obtain better insight into the molecular mechanisms associated with the process of pigmentation of yellow-skinned broilers reared under intensive conditions, a total of six-hundred Ma-Huang chickens was randomly selected in a single slaughterhouse, the color measurements were carried out on both cloaca(alive) and five different part after slaughtering adopting the L* a* b* system and using a 3nh-NH310 colorimeter, color values from areas of the chicken skin pear each image automatically retrieved by MATLAB, production and slaughtering traits were also measured, comparative transcriptomic analysis of high yellowness(s_deep) versus low yellowness(s_light) skin was performed using the Illumina Hiseq 4000. Average values of the cloaca(alive), cloaca (hair removal), thigh, shank and abdominal fat were 8.98, 7.66, 2.62, 7.29 and 12.86, respectively. The better production and slaughtering traits were observed in higher skin yellowness chicken. Yellowness values of the cloaca(alive) and after slaughtering were significantly correlated (p < 0.05), suggesting that the color of after slaughtering evaluation may be carried out on cloaca(alive). A total of 19061 unigenes were assembled from the reads obtained from the skin of two groups, 882 unigenes were differentially expressed between s_deep and s_light (Fold change ≥ 2, Adjusted P <= 0.001), 612 that up-regulated and 270 that down-regulated genes in s_deep skin, as compared with s_light skin. Twelve promising candidate genes may play an important role in the pigmentation of chicken skin, i.e. GPR143, PMEL, TYR, CYP11A1, TECRL, ACACB, TLR2B, ALDH1A3, FHL2, TECRL, DUOX2, SMOC1 were included. Furthermore, some important functional pathways were revealed, such as the biological process, cellular component and molecular function, which appear to be much activity in skin pigmentation. Our data provide a valuable resource for identifying genes whose functions are critical to skin pigmentation, facilitate understanding the molecular mechanisms of the skin color variation on yellow-skinned broiler chickens under commercial conditions, accelerate the molecular selection of the specific strain on consistent skin colors which allow reduction in pigment use to achieve the skin acceptance by the consumer.

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Integrative functional genomic analyses identify novel genetic variants influencing skin pigmentation in indigenous Africans [RNA-seq]

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