Haijing Yu

Evolution of the human-specific microRNA miR-941

MicroRNA-mediated gene regulation is important in many physiological processes. Here we explore the roles of a microRNA, miR-941, in human evolution. We find that miR-941 emerged de novo in the human lineage, between six and one million years ago, from an evolutionarily volatile tandem repeat sequence. Its copy-number remains polymorphic in humans and shows a trend for decreasing copy-number with migration out of Africa. Emergence of miR-941 was accompanied by accelerated loss of miR-941-binding sites, presumably to escape regulation. We further show that miR-941 is highly expressed in pluripotent cells, repressed upon differentiation and preferentially targets genes in hedgehog- and insulin-signalling pathways, thus suggesting roles in cellular differentiation. Human-specific effects of miR-941 regulation are detectable in the brain and affect genes involved in neurotransmitter signalling. Taken together, these results implicate miR-941 in human evolution, and provide an example of rapid regulatory evolution in the human linage.

A Young Drosophila Duplicate Gene Plays Essential Roles in Spermatogenesis by Regulating Several Y-Linked Male Fertility Genes

Gene duplication is supposed to be the major source for genetic innovations. However, how a new duplicate gene acquires functions by integrating into a pathway and results in adaptively important phenotypes has remained largely unknown. Here, we investigated the biological roles and the underlying molecular mechanism of the young kep1 gene family in the Drosophila melanogaster species subgroup to understand the origin and evolution of new genes with new functions. Sequence and expression analysis demonstrates that one of the new duplicates, nsr (novel spermatogenesis regulator), exhibits positive selection signals and novel subcellular localization pattern. Targeted mutagenesis and whole-transcriptome sequencing analysis provide evidence that nsr is required for male reproduction associated with sperm individualization, coiling, and structural integrity of the sperm axoneme via regulation of several Y chromosome fertility genes post-transcriptionally. The absence of nsr-like expression pattern and the presence of the corresponding cis-regulatory elements of the parental gene kep1 in the pre-duplication species Drosophila yakuba indicate that kep1 might not be ancestrally required for male functions and that nsr possibly has experienced the neofunctionalization process, facilitated by changes of trans-regulatory repertories. These findings not only present a comprehensive picture about the evolution of a new duplicate gene but also show that recently originated duplicate genes can acquire multiple biological roles and establish novel functional pathways by regulating essential genes.

Polymorphisms in PPARD, PPARG and APM1 associated with four types of traditional Chinese medicine constitutions.

Based on the theory of constitution of Traditional Chinese Medicine (TCM), the human population is divided into nine constitutions including one balanced constitution (Normality) and eight unbalanced constitutions (Yang-deficiency, Yin-deficiency, Phlegm-wetness, Qi-deficiency, Wetness-heat, Blood stasis, Depressed constitution, and Inherited special constitution). Different constitutions have specific metabolic features and different susceptibility to certain diseases. However, whether a genetic basis accounts for such constitution classification is yet to be determined. Here we performed a genetic study to assess the association between genetic variations of metabolic genes including PPARD, PPARG and APM1 and the constitutions. A total of 233 individuals of the Han population in China were classified into four groups, Normality, Yang-deficiency, Yin-deficiency and Phlegm-wetness with whom 23 single nucleotide polymorphisms (SNPs) in the three genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Biased distribution of PPARD rs2267669 and rs2076167, APM1 rs7627128 and rs1063539 in Yang-deficiency, PPARG Pro12Ala in Yin-deficiency and PPARD rs2076167, APM1 rs266729 and rs7627128 in Phlegm-wetness were observed. The frequencies of Haplotype13 (Hap13) of PPARG in Yin-deficiency, Hap25 of APM1 in Yang-deficiency and Hap2 of PPARD and Hap14 of PPARG in Phlegm-wetness, were significantly different from those in Normality, suggesting those might be group-associated haplotypes. These results suggested that single SNP and haplotypes of PPARD, PPARG and APM1 may underlie the genetic basis of the constitutions classified in TCM.

Rapid Functional Divergence of a Newly Evolved Polyubiquitin Gene in Drosophila and Its Role in the Trade-off between Male Fecundity and Lifespan

The cost of reproduction is a pivotal trade-off with various biological processes during the evolution of organisms. However, the genes and molecular mechanisms underlying the evolution of balancing reproductive capacity and its cost are still largely unknown. Here, we present a comprehensive study on the evolution, expression, and biological functions of a newly evolved pair of X-linked polyubiquitin tandemly duplicated genes, CG32744 and CG11700, of which the duplication event occurred in Drosophila melanogaster lineage after the split from D. simulans clade. We found that CG32744 retains conserved polyubiquitin-coding sequences across Drosophila species and is ubiquitously expressed, whereas CG11700 has accumulated numerous amino acid changes and shows a male-specific expression pattern. Null mutants of CG11700 have a higher male fecundity but shorter lifespan, whereas its overexpression decreases male fecundity. In contrast, the null mutants of the peptide-conserved CG32744 do not exhibit such phenotypes. These results suggest that CG11700 might have experienced neofunctionalization and evolved important functions in the trade-off between male fecundity and lifespan and that CG32744 likely has retained the ancestral function.

Association of WNK1 exon 1 polymorphisms with essential hypertension in Hani and Yi minorities of China

The association of polymorphisms in exon 1 of the WNK1 gene with essential hypertension in the minority groups of Hani and Yi of China was investigated in the case-control study. The sequence of 1257bp containing the WNK1 gene exon 1 was determined in 1307 individuals (649 essential hypertension subjects and 658 controls) to identify SNPs in Hani and Yi minority groups. Four of eleven previously known SNPs (rs3168640, rs11885, rs11554421 and rs34880640) were identified. The SNP analysis indicated that SNPs rs11885 and rs11554421 were significantly associated with hypertension in both Hani and Yi populations, and rs34880640 was significantly associated with hypertension in Hani but not in Yi population, adjusted for covariates. Haplotype analysis indicated that the haplotype H1 significantly decreased the risk of hypertension in both populations. These results suggested that WNK1 polymorphisms were involved in the predisposition of essential hypertension in Hani and Yi populations and its effects showed a clear population specificity. This finding supported the importance of population specificity in determining the genetic factors associated with diseases and thus disease treatment.

Recently evolved tumor suppressor transcript TP73-AS1 functions as sponge of human-specific miR-941

Abstract MicroRNA (miRNA) sponges are vital components of posttranscriptional gene regulation. Yet, only a limited number of miRNA sponges have been identified. Here, we show that the recently evolved noncoding tumor suppressor transcript, antisense RNA to TP73 gene (TP73‐AS1), functions as a natural sponge of human‐specific miRNA miR‐941. We find unusually nine high‐affinity miR‐941 binding sites clustering within 1 kb region on TP73‐AS1, which forms miR‐941 sponge region. This sponge region displays increased sequence constraint only in humans, and its formation can be traced to the tandem expansion of a 71‐nt‐long sequence containing a single miR‐941 binding site in old world monkeys. We further confirm TP73‐AS1 functions as an efficient miR‐941 sponge based on massive transcriptome data analyses, wound‐healing assay, and Argonaute protein immunoprecipitation experiments conducted in cell lines. The expression of miR‐941 and its sponge correlate inversely across multiple healthy and cancerous tissues, with miR‐941 being highly expressed in tumors and preferentially repressing tumor suppressors. Thus, the TP73‐AS1 and miR‐941 duo represents an unusual case of the extremely rapid evolution of noncoding regulators controlling cell migration, proliferation, and tumorigenesis.