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Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (∼39.7%), West Asian (∼28.6%), Siberian (∼23.6%), and South Asian (∼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5 , OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR , SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that metabolic reprogramming of cancer cells supports the energy and metabolic demands during tumor metastasis. However, the metabolic alterations underlying lymph node metastasis (LNM) of cervical cancer (CCa) have not been well recognized. In the present study, it is found that lymphatic metastatic CCa cells have reduced dependency on glucose and glycolysis but increased fatty acid oxidation (FAO). Inhibition of carnitine palmitoyl transferase 1A (CPT1A) significantly compromises palmitate‐induced cell stemness. Mechanistically, FAO‐derived acetyl‐CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of stemness genes, increasing stemness and nodal metastasis in the lipid‐rich nodal environment. Genetic and pharmacological loss of CPT1A function markedly suppresses the metastatic colonization of CCa cells in tumor‐draining lymph nodes. Together, these findings propose an effective method of cancer therapy by targeting FAO in patients with CCa and lymph node metastasis. [ABSTRACT FROM AUTHOR]

WEE1 has emerged as an attractive target in epithelial ovarian cancer (EOC), but how EOC cells may alter their sensitivity to WEE1 inhibition remains unclear. Here, through a cell cycle machinery- related gene RNAi screen, we found that targeting outer dense fiber of sperm tails 2-like (ODF2L) was a synthetic lethal partner with WEE1 kinase inhibition in EOC cells. Knockdown of ODF2L robustly sensitized cells to treatment with the WEE1 inhibitor AZD1775 in EOC cell lines in vitro as well as in xenografts in vivo. Mechanistically, the increased sensitivity to WEE1 inhibition upon ODF2L loss was accompanied by accumulated DNA damage. ODF2L licensed the recruitment of PKMYT1, a functionally redundant kinase of WEE1, to the CDK1-cyclin B complex and thus restricted the activity of CDK1 when WEE1 was inhibited. Clinically, upregulation of ODF2L correlated with CDK1 activity, DNA damage levels, and sensitivity to WEE1 inhibition in patient-derived EOC cells. Moreover, ODF2L levels predicted the response to WEE1 inhibition in an EOC patient- derived xenograft model. Combination treatment with tumor-targeted lipid nanoparticles that packaged ODF2L siRNA and AZD1775 led to the synergistic attenuation of tumor growth in the ID8 ovarian cancer syngeneic mouse model. These data suggest that WEE1 inhibition is a promising precision therapeutic strategy for EOC cells expressing low levels of ODF2L., Introduction Epithelial ovarian cancer (EOC), the most common subtype of ovarian cancer, ranks fifth in cancer-related deaths among women (1, 2). EOC is more than a single disease, as it [...]

Population admixture results in genome-wide combinations of genetic variants derived from different ancestral populations of distinct ancestry, thus providing a unique opportunity for understanding the genetic determinants of phenotypic variation in humans. Here, we used whole-genome sequencing of 92 individuals with high coverage (30–60×) to systematically investigate genomic diversity in the Uyghurs living in Xinjiang, China (XJU), an admixed population of both European-like and East-Asian-like ancestry. The XJU population shows greater genetic diversity, especially a higher proportion of rare variants, compared with their ancestral source populations, corresponding to greater phenotypic diversity of XJU. Admixture-induced functional variants in EDAR were associated with the diversity of facial morphology in XJU. Interestingly, the interaction of functional variants between SLC24A5 and OCA2 likely influences the diversity of skin pigmentation. Notably, selection has seemingly been relaxed or canceled in several genes with significantly biased ancestry, such as HERC2 – OCA2. Moreover, signatures of post-admixture adaptation in XJU were identified, including genes related to metabolism (e.g. CYP2D6), digestion (e.g. COL11A1), olfactory perception (e.g. ANO2) and immunity (e.g. HLA). Our results demonstrated population admixture as a driving force, locally or globally, in shaping human genetic and phenotypic diversity as well as in adaptive evolution. [ABSTRACT FROM AUTHOR]