【求助】非编码序列突变与人类遗传病

近年逐渐发现非编码序列突变在人类遗传病中发挥重要作用，此类序列突变如何致病？对其致病性如何研究判定？

这些都是医学遗传学上的内容。建议楼主留意一下教材和中文综述。

In the human genome , variations of non-coding seqences including 5’UTRs，3’UTRs，promoters，introns ，long-rang cis-control elements，gene desert sequences ，ncRNA genes , psuedogenes , were responsible for the men genetic differences . These elements played a cricial role in two major important biological process - gene expressions and protein modifications. And sometimes , when these elements occurred point mutations/micro-indels/structure variations , these could led to genomic/epigenetic dysfunction and finally caused typical phenotypes from mild to sever . Omim diseases , complex diseases , cancers and many other dysfunctions were associated with them based on the sesearches nowadays .

In the fields of clarifying the internal mechnisms of these variations , we faced numorous challenges . How to mapping these variations? As I see , no single method could afford to comprehansive identify them . Recently the development of high-roughout methods such as GWLS(genome wide linkage study)/GWAS(genome wide association study)/NGS(next gene sequencing)/DGE(digital gene expression) , instead of conditional PAGE-based STS/SNP marker genotyping , gave the new insight for fine-mapping these non-coding seqences mutations . But these methods could not exactly validate the causaltive relationship between genotypes and phenotypes .

Functional evidences were the golden criterion , but these seems to beyond the geneticists’ ability in the past few years . Nowadays most masterpiece published on Cell/Nature/Science and other top journals were merely linked one aspect . So combinate the offshoot of all genetic elements absorbed from biochemistry,cell biology,development biology and computer science was the irresistible general trend. All the non-coding elements in human genomes could harbe the non-coding RNA genes , not strange for us , microRNAs , anti-sense RNAs , psuedogenes or long non-coding RNAs etc. Recently distinct groups found the tag rs6983267 was associated with prostate and colorectal cancer , followed with a series of functional study demonstrated it could show long-range interaction with myc to enhance the Wnt signaling pathway . The long non-coding DNA elements , in a sense long range cis-control elements , had been fine explained in regulating SHH , PAX6 , SOX9 gene spatiotemporal expression . Last month , an article on Nature demonstrated the 9p21 non-coding took part in artery diseases using the Cre-LoxP mediated gene targeting in mice . Over a thousand of highly conserved large non-coding RNAs were mapped in human genomes . Continuing advances in transcriptomics are resulting in ncRNA being recognized as an important functional expression of the genome. Non-coding RNAs exert its impact on chromatin modification(HoxD cluster) , X chromosome inactiviton(Xist) , transcriptional regulation(CyclinD1) and post-transcriptional modification(SIP1) . Comparablely micoRNAs were the most understanded . microRNAs’ target site mutations could enhance or reduce the gene expression profiles , paticular in cancers . Not only the UTR mutations but the CDS of genes were linked to them , such as SOX2 , OCT4 . Many serum microRNAs selected by DGE analysis had potential diagnosis values in special cancers’ predication. A better illustrating the non-coding elements’ fuction in human genome remains to be.