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2018 Victor A. McKusick Leadership Award: Molecular Mechanisms for Genomic and Chromosomal Rearrangements.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-03-07 , DOI: 10.1016/j.ajhg.2018.12.018 James R Lupski 1
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-03-07 , DOI: 10.1016/j.ajhg.2018.12.018 James R Lupski 1
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Thank you, Dave Valle, for that kind introduction and thanks to our Society for this terrific honor of the McKusick Leadership Award, which has very special meaning coming from the Society in which I grew up professionally. Experiential advice for the students, postdocs, and junior faculty that are present here today is that often some of your most important mentors are not at your institution, but rather sitting next to you here at the American Society of Human Genetics Annual Meeting; introduce yourself and get involved in your Society. When we think of the human genome and how specific variation at a locus may result in different phenotypic outcomes, it is perhaps a good analogy to think of a diploid (i.e., two copies of each volume) 23-volume encyclopedia of the information required to sustain biological life (Figure 1). In this encyclopedia one has several “variant types:” a chromosome might be thought of as one volume of the encyclopedia. Single, simple, or small nucleotide variants (SNVs; Watson-Crick base pair changes), a type of variation that has also been referred to as a SNP (single-nucleotide polymorphism), could be analogized as a change in the alphabet that could change the meaning of a word. Likewise, indels, or small (<50 bp) insertion/deletions of Watson-Crick base pairs, could also result in a change in the meaning of the language of genetics by altering a word (codon), sentence (exon), or paragraph (gene) (Figure 1). However, there is another type or category of genetic and genomic variation, of a size between that which can be visualized microscopically by changes to a chromosome and that readily discerned molecularly by short read nucleotide sequencing—i.e., structural variants (SVs), including copy number variants (CNVs) (Figure 1). These CNVs can alter the gene copy-number and dosage at a genetic locus, causing deviations from the normal diploid state. Such deviations can have implications for haploinsufficiency and triplosensitivity disease traits; affect the interpretation of marker genotypes at a locus, sometimes distorting the results of linkage analyses;4,5Matise T.C.Chakravarti A.Patel P.I.Lupski J.R.Nelis E.Timmerman V.Van Broeckhoven C.Weeks D.E.Detection of tandem duplications and implications for linkage analysis.Am. J. Hum. Genet.1994;54:1110-1121PubMedGoogle Scholar,6Lupski J.R.2002 Curt Stern Award Address. Genomic disorders recombination-based disease resulting from genomic architecture.Am. J. Hum. Genet.2003;72:246-252AbstractFull TextFull Text PDFPubMedScopus (0)Google Scholarpotentially inflate the significance of association studies;7Liu J.Zhou Y.Liu S.Song X.Yang X.Z.Fan Y.Chen W.Akdemir Z.C.Yan Z.Zuo Y.et al.J.LiuY.ZhouS.LiuX.SongX.Z.YangY.FanW.ChenZ.C.AkdemirZ.YanY.ZuoDISCO (Deciphering disorders Involving Scoliosis and COmorbidities) StudyThe coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.Hum. Genet.2018;137:553-567CrossrefPubMedScopus (1)Google Scholarand if involving genes or even just single exons may contribute to disease gene discovery8Gambin T.Yuan B.Bi W.Liu P.Rosenfeld J.A.Coban-Akdemir Z.Pursley A.N.Nagamani S.C.S.Marom R.Golla S.et al.Identification of novel candidate disease genes fromde novoexonic copy number variants.Genome Med.2017;9:83CrossrefPubMedScopus (7)Google Scholarand molecular diagnoses (CNV + SNV).9Yang Y.Muzny D.M.Xia F.Niu Z.Person R.Ding Y.Ward P.Braxton A.Wang M.Buhay C.et al.Molecular findings among patients referred for clinical whole-exome sequencing.JAMA.2014;312:1870-1879CrossrefPubMedScopus (536)Google Scholar,10Bayer D.K.Martinez C.A.Sorte H.S.Forbes L.R.Demmler-Harrison G.J.Hanson I.C.Pearson N.M.Noroski L.M.Zaki S.R.Bellini W.J.et al.Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations inIL7Rdetected by tandem whole exome sequencing and chromosomal microarray.Clin. Exp. Immunol.2014;178:459-469CrossrefPubMedScopus (22)Google Scholar
中文翻译：
2018 Victor A. McKusick 领导奖：基因组和染色体重排的分子机制。
谢谢戴夫·瓦莱（Dave Valle）的热情介绍，并感谢我们的协会授予麦库西克领导力奖这一殊荣，这对于我职业成长的协会来说具有非常特殊的意义。对今天在座的学生、博士后和初级教师的经验建议是，你们最重要的导师通常不在你们的机构，而是在美国人类遗传学学会年会上坐在你们旁边；自我介绍并参与您的协会。当我们思考人类基因组以及某个位点的特定变异如何导致不同的表型结果时，可以将二倍体（即每卷两个副本）23卷的百科全书视为一个很好的类比，其中包含了所需的信息。维持生物生命（图1）。在这本百科全书中，一个人有几种“变体类型”：一条染色体可能被认为是百科全书的一卷。单个、简单或小核苷酸变异（SNV；Watson-Crick 碱基对变化）是一种变异类型，也被称为 SNP（单核苷酸多态性），可以类比为字母表中的变化，改变一个词的含义。同样，插入/缺失，或 Watson-Crick 碱基对的小 (<50 bp) 插入/删除，也可能通过改变单词（密码子）、句子（外显子）或段落而导致遗传学语言含义的变化。 （基因）（图1）。然而，还有另一种类型或类别的遗传和基因组变异，其大小介于可以通过染色体变化在显微镜下观察到的变异和通过短读长核苷酸测序在分子上容易辨别的变异，即结构变异（SV），包括拷贝数量变异 (CNV)（图 1）。 这些 CNV 可以改变基因位点的基因拷贝数和剂量，导致与正常二倍体状态的偏差。这种偏差可能会对单倍体不足和三倍敏感性疾病特征产生影响；影响某个位点标记基因型的解释，有时会扭曲连锁分析的结果；4,5Matise TCChakravarti A.Patel PILupski JRNelis E.Timmerman V.Van Broeckhoven C.Weeks DE串联重复的检测及其对连锁分析的影响。 J.哼。 Genet.1994；54：1110-1121PubMedGoogle Scholar，6Lupski JR2002 Curt Stern 奖演讲。基因组疾病由基因组结构引起的基于重组的疾病。Am。 J.哼。 Genet.2003;72:246-252AbstractFull Text全文PDFPubMedScopus (0)Google Scholar潜在地夸大了关联研究的重要性；7Liu J.Zhou Y.Liu S.Song X.Yang XZFan Y.Chen W.Akdemir ZCYan Z.Zuo Y.等人J.LiuY.ZhouS.LiuX.SongX.Z.YangY.FanW.ChenZ.C.AkdemirZ.YanY.ZuoDISCO（解读涉及脊柱侧弯和合并症的疾病）研究拷贝数变异（CNV）和单核苷酸多态性的共存（某个基因座上的 SNP 可能会导致 SNP 与疾病关联的重要性计算出现偏差。 Genet.2018;137:553-567CrossrefPubMedScopus (1)Google Scholarand 如果涉及基因甚至仅单个外显子可能有助于疾病基因的发现8Gambin T.Yuan B.Bi W.Liu P.Rosenfeld JACoban-Akdemir Z.Pursley ANNagamani SCSMarom R. Golla S.et al.Identification of new候选疾病基因来自从头外显子拷贝数变异。Genome Med.2017;9:83CrossrefPubMedScopus (7)Google Scholarand分子诊断(CNV + SNV).9Yang Y.Muzny DMXia F.Niu Z.Person R.Ding Y.Ward P.Braxton A.Wang M.Buhay C.et al。转诊进行临床全外显子组测序的患者的分子发现。JAMA.2014;312:1870-1879CrossrefPubMedScopus (536)Google Scholar,10Bayer DKMartinez CASorte HSForbes LRDemmler-Harrison GJHanson ICPearson NMNoroski LMZaki SRBellini WJet al.疫苗相关的水痘和风疹感染于通过串联全外显子组测序和染色体微阵列检测到严重联合免疫缺陷伴孤立性 CD4 淋巴细胞减少症和 IL7R 突变。过期。免疫学。2014;178:459-469CrossrefPubMedScopus (22)谷歌学术
更新日期：2019-03-07
中文翻译：
2018 Victor A. McKusick 领导奖：基因组和染色体重排的分子机制。
谢谢戴夫·瓦莱（Dave Valle）的热情介绍，并感谢我们的协会授予麦库西克领导力奖这一殊荣，这对于我职业成长的协会来说具有非常特殊的意义。对今天在座的学生、博士后和初级教师的经验建议是，你们最重要的导师通常不在你们的机构，而是在美国人类遗传学学会年会上坐在你们旁边；自我介绍并参与您的协会。当我们思考人类基因组以及某个位点的特定变异如何导致不同的表型结果时，可以将二倍体（即每卷两个副本）23卷的百科全书视为一个很好的类比，其中包含了所需的信息。维持生物生命（图1）。在这本百科全书中，一个人有几种“变体类型”：一条染色体可能被认为是百科全书的一卷。单个、简单或小核苷酸变异（SNV；Watson-Crick 碱基对变化）是一种变异类型，也被称为 SNP（单核苷酸多态性），可以类比为字母表中的变化，改变一个词的含义。同样，插入/缺失，或 Watson-Crick 碱基对的小 (<50 bp) 插入/删除，也可能通过改变单词（密码子）、句子（外显子）或段落而导致遗传学语言含义的变化。 （基因）（图1）。然而，还有另一种类型或类别的遗传和基因组变异，其大小介于可以通过染色体变化在显微镜下观察到的变异和通过短读长核苷酸测序在分子上容易辨别的变异，即结构变异（SV），包括拷贝数量变异 (CNV)（图 1）。 这些 CNV 可以改变基因位点的基因拷贝数和剂量，导致与正常二倍体状态的偏差。这种偏差可能会对单倍体不足和三倍敏感性疾病特征产生影响；影响某个位点标记基因型的解释，有时会扭曲连锁分析的结果；4,5Matise TCChakravarti A.Patel PILupski JRNelis E.Timmerman V.Van Broeckhoven C.Weeks DE串联重复的检测及其对连锁分析的影响。 J.哼。 Genet.1994；54：1110-1121PubMedGoogle Scholar，6Lupski JR2002 Curt Stern 奖演讲。基因组疾病由基因组结构引起的基于重组的疾病。Am。 J.哼。 Genet.2003;72:246-252AbstractFull Text全文PDFPubMedScopus (0)Google Scholar潜在地夸大了关联研究的重要性；7Liu J.Zhou Y.Liu S.Song X.Yang XZFan Y.Chen W.Akdemir ZCYan Z.Zuo Y.等人J.LiuY.ZhouS.LiuX.SongX.Z.YangY.FanW.ChenZ.C.AkdemirZ.YanY.ZuoDISCO（解读涉及脊柱侧弯和合并症的疾病）研究拷贝数变异（CNV）和单核苷酸多态性的共存（某个基因座上的 SNP 可能会导致 SNP 与疾病关联的重要性计算出现偏差。 Genet.2018;137:553-567CrossrefPubMedScopus (1)Google Scholarand 如果涉及基因甚至仅单个外显子可能有助于疾病基因的发现8Gambin T.Yuan B.Bi W.Liu P.Rosenfeld JACoban-Akdemir Z.Pursley ANNagamani SCSMarom R. Golla S.et al.Identification of new候选疾病基因来自从头外显子拷贝数变异。Genome Med.2017;9:83CrossrefPubMedScopus (7)Google Scholarand分子诊断(CNV + SNV).9Yang Y.Muzny DMXia F.Niu Z.Person R.Ding Y.Ward P.Braxton A.Wang M.Buhay C.et al。转诊进行临床全外显子组测序的患者的分子发现。JAMA.2014;312:1870-1879CrossrefPubMedScopus (536)Google Scholar,10Bayer DKMartinez CASorte HSForbes LRDemmler-Harrison GJHanson ICPearson NMNoroski LMZaki SRBellini WJet al.疫苗相关的水痘和风疹感染于通过串联全外显子组测序和染色体微阵列检测到严重联合免疫缺陷伴孤立性 CD4 淋巴细胞减少症和 IL7R 突变。过期。免疫学。2014;178:459-469CrossrefPubMedScopus (22)谷歌学术
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