Identification Of CDH11 As An ASD Risk Gene By Matched-gene Coexpression Analysis And Mouse Behavioral Studies

Autism spectrum disorder(ASD)is a behaviorally diagnosed disease with a complex genetic basis.Multiple genetic approaches have revealed a large group of susceptibility genes whose mutations or copy number variations(CNV)may be associated with ASD.However,for many recently identified risk genes,their functions in the brain either have never been studied or are largely unknown.A causal effect of gene variations on autism traits remains to be validated at behavioral and neurobiological levels.Therefore,in order to prioritize experimental research to genes and signaling pathways of high relevance to autism biology,a method for efficient evaluation of the functional importance of a large group of newly identified risk genes is vital to current ASD research.Several studies have demonstrated that genes with similar co-expression patterns are likely to function together in common cellular pathways.Based on this concept,genome-wide gene co-expression analysis has been developed as a powerful tool for identifying convergent signaling pathways of risk genes associated with ASD.However,how to screen for functionally important co-expression relationship in the gene coexpression analysis remains unclear.Cadherin family members are known to play important roles in multiple developmental processes,including cell proliferation,polarization,neuronal migration,axon projection,dendrite arborization,and synapse assembly.Like most recently reported risk genes,it is largely unclear which cadherin family members are functionally important in ASD-relevant circuits and which ASD-relevant brain areas may be affected by genetic alterations of cadherins.In the present study,we unexpectedly discovered that several gene features profoundly affect a gene’s genome-wide co-expression profile.Based on this effect,we developed a “matched-gene co-expression analysis” to detect biologically important gene co-expression relationships.Using this approach and animal behavioral analysis,we discovered that CDH11 may be an important risk gene of ASD.Main findings:1.Gene features affect a gene’s genome-wide co-expression profile.We discovered that in typically developing brains,a gene’s m RNA abundance level,g DNA size,m RNA size,and GC content in the coding region profoundly affect its co-expression profile across the whole genome,and these effects are highly conserved in different developing stages,different genders and different brain regions.2.Matched-gene co-expression analysis can better discover the molecular pathways closely relevant to ASD.We developed a data analysis framework to screen for functionally important gene co-expression relationships by statistically correcting the influence of m RNA abundance level,g DNA size,m RNA size and GC content in coding region on the gene co-expression measure,and we called this method “matched-gene co-expression analysis”.Using this unbiased approach,we demonstrated the convergent expression of hc ASDs in developing brains.Combining results under four different matched conditions(Tetra-M),we identified 2911 genes that exhibited significant co-expression with hc ASDs,and found that these genes are enriched in signaling pathways that are known to be closely relevant to ASD.3.Identification of CDH11 as an ASD risk gene by matched-gene co-expression analysis and mouse behavioral studies.Using matched-gene co-expression analysis,we found a group of cadherin family members exhibit significant co-expression with hc ASDs.Further analysis of two classical cadherins,CDH11 and CDH9,revealed significant co-expression of CDH11,but not CDH9,with hc ASDs,suggesting the participation of CDH11 in ASD-relevant circuits.Consistently,CDH11-null mice,but not CDH9-null mice,exhibited multiple autistic-like behavioral alterations.Taken together,“matched-gene co-expression analysis” may help us to screen for functionally important ASD risk genes more objectively and accurately,and to discover ASD-relevant convergent signaling pathways,which will lead to the identification of novel intervention targets for the ASD therapy.It is worth further research and optimization.In addition,further study of the important ASD risk gene CDH11 will help us better understand the new ASD subtypes and their pathogenesis.