Most plants are polyploid due to whole-genome duplications （WGD） and can thus have duplicated genes. Following a WGD, paralogs are often fractionated （lost） and few duplicate pairs remain. Little attention has bee...Most plants are polyploid due to whole-genome duplications （WGD） and can thus have duplicated genes. Following a WGD, paralogs are often fractionated （lost） and few duplicate pairs remain. Little attention has been paid to the role of DNA methylation in the functional divergence of paralogous genes. Using high- resolution methylation maps of accessions of domesticated and wild soybean, we show that in soybean, a recent paleopolyploid with many paralogs, DNA methylation likely contributed to the elimination of ge- netic redundancy of polyploidy-derived gene paralogs. Transcriptionally silenced paralogs exhibit partic- ular genomic features as they are often associated with proximal transposable elements （TEs） and are pref- erentially located in pericentromeres, likely due to gene movement during evolution. Additionally, we provide evidence that gene methylation associated with proximal TEs is implicated in the divergence of expression profiles between orthologous genes of wild and domesticated soybean, and within populations.展开更多
Side effects from targeted drugs remain a serious conccrn. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which arc highly homologous in sequences and have similar struct...Side effects from targeted drugs remain a serious conccrn. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which arc highly homologous in sequences and have similar structures and drug-binding pockets. To identify targctablc differences between paralogs, we analyzed two types （type-I and type-ll） of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors （GPCRs） at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor （GCGR） and glucagon-like peptide-I receptor （GLP-I R）, exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-ll alnino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR. which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-IR. The divergent features between GCGR and GLP-I R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.展开更多
Spinal muscular atrophy(SMA)is caused by dysfunction of the alpha motor neurons of the spinal cord.It is an autosomal recessive disease associated to the SMN1 gene,located in the subtelomeric region of 5q13.A paralog ...Spinal muscular atrophy(SMA)is caused by dysfunction of the alpha motor neurons of the spinal cord.It is an autosomal recessive disease associated to the SMN1 gene,located in the subtelomeric region of 5q13.A paralog SMN2 gene is located at the centromeric region of the same chromosome,which apparently originated by an ancestral inverted duplication occurring only in humans.The exon sequence differs in two nucleotides in exon 7 and exon 8,which leads to an SMN2 transcript that lacks exon 7 and results in a truncated protein.Part(10%)of the SMN2 transcripts avoids the splicing of exon 7 but most of the copies are dysfunctional.In a disease scenario,the more SMN2 copies the higher possibility to restore at least partly the effects of SMN1 deficiency.Some therapeutic approaches are being developed to increase the expression of SMN2.To determine the number of SMN1 and SMN2 copies,the methodology must distinguish accurately between both genes.In this work,we present the results obtained using multiplex ligation-dependent probe amplification(MLPA)in 60 SMA suspected patients/carriers derived from different regions of Argentina.In 32 of these DNA samples we found alterations in SMN1.Among these,16 presented a heterozygous deletion(carrier status)and 14 an homozygous deletion(patient status)in exon 7 and 8 of SMN1.In one case,exon 7 was found homozygously deleted but exon 8 presented a single copy,and in another case,exon 7 was found heterozygously deleted while exon 8 was normal.Almost half of the patients(7/15)presented a normal diploid number of SMN2 while the other half(8/15)presented an increased number.In this work we showed how a probe-based methodology such as MLPA was able to distinguish between the paralog genes and determine the amount of copies in DNA samples from suspected patients/carriers of SMA.展开更多
文摘Most plants are polyploid due to whole-genome duplications （WGD） and can thus have duplicated genes. Following a WGD, paralogs are often fractionated （lost） and few duplicate pairs remain. Little attention has been paid to the role of DNA methylation in the functional divergence of paralogous genes. Using high- resolution methylation maps of accessions of domesticated and wild soybean, we show that in soybean, a recent paleopolyploid with many paralogs, DNA methylation likely contributed to the elimination of ge- netic redundancy of polyploidy-derived gene paralogs. Transcriptionally silenced paralogs exhibit partic- ular genomic features as they are often associated with proximal transposable elements （TEs） and are pref- erentially located in pericentromeres, likely due to gene movement during evolution. Additionally, we provide evidence that gene methylation associated with proximal TEs is implicated in the divergence of expression profiles between orthologous genes of wild and domesticated soybean, and within populations.
基金supported by a grant from the National Natural Science Foundation of China(Grant No.31571355 and 31301034)supported by Fudan University,ChinaIowa State University,United States
文摘Side effects from targeted drugs remain a serious conccrn. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which arc highly homologous in sequences and have similar structures and drug-binding pockets. To identify targctablc differences between paralogs, we analyzed two types （type-I and type-ll） of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors （GPCRs） at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor （GCGR） and glucagon-like peptide-I receptor （GLP-I R）, exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-ll alnino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR. which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-IR. The divergent features between GCGR and GLP-I R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.
文摘Spinal muscular atrophy(SMA)is caused by dysfunction of the alpha motor neurons of the spinal cord.It is an autosomal recessive disease associated to the SMN1 gene,located in the subtelomeric region of 5q13.A paralog SMN2 gene is located at the centromeric region of the same chromosome,which apparently originated by an ancestral inverted duplication occurring only in humans.The exon sequence differs in two nucleotides in exon 7 and exon 8,which leads to an SMN2 transcript that lacks exon 7 and results in a truncated protein.Part(10%)of the SMN2 transcripts avoids the splicing of exon 7 but most of the copies are dysfunctional.In a disease scenario,the more SMN2 copies the higher possibility to restore at least partly the effects of SMN1 deficiency.Some therapeutic approaches are being developed to increase the expression of SMN2.To determine the number of SMN1 and SMN2 copies,the methodology must distinguish accurately between both genes.In this work,we present the results obtained using multiplex ligation-dependent probe amplification(MLPA)in 60 SMA suspected patients/carriers derived from different regions of Argentina.In 32 of these DNA samples we found alterations in SMN1.Among these,16 presented a heterozygous deletion(carrier status)and 14 an homozygous deletion(patient status)in exon 7 and 8 of SMN1.In one case,exon 7 was found homozygously deleted but exon 8 presented a single copy,and in another case,exon 7 was found heterozygously deleted while exon 8 was normal.Almost half of the patients(7/15)presented a normal diploid number of SMN2 while the other half(8/15)presented an increased number.In this work we showed how a probe-based methodology such as MLPA was able to distinguish between the paralog genes and determine the amount of copies in DNA samples from suspected patients/carriers of SMA.
