Unit 2 Gene and Its Application
Gene Study Helps Unravel Biology of Alcoholism
1 Genomic association studies can help scientists pick out target genes and biologic
al pathways for further investigation, but they are not the end-all tools to explain disease mechanisms. 2 A new genomewide association study (GWAS ① ) has found several mutations linked to increased susceptibility for developing alcohol dependence, bringing scientists a step closer to understanding the complex biological mechanisms of alcohol use disorders. 3 Two single nucleotide polymorphisms (SNPs②), both located on the chromosomal region 2p35, had the highest degree of association with alcohol dependence in a relatively homogenous patient population. These SNPs are located near the PECR gene, which encodes an enzyme (peroxisomal trans-2-enoyl-coA reductase) involved in fatty-acid metabolism, particularly when the body’s energy supply is switched from glucose to fat. 4 A third SNP with a slightly lower association with alcohol dependence is located within the PECR gene. These three variants are “in strong linkage disequilibrium, or LD, meaning that the same variants at different loci almost always appear together,” Marcella Rietschel, M.D. ③, the senior author of the study, told Psychiatric News④. “So it is very likely—but still not certain—that the PECR gene is involved [in alcohol dependence].” 5 Rietschel is a professor of genetic epidemiology in psychiatry at the Central Institute of Mental Health Mannheim at the University of Heidelberg⑤, Germany. 6 This chromosomal region has been implicated in alcohol dependence in previous research. The PECR gene is expressed most heavily in the liver, but very little in the brain. “As alcohol does not act only on the brain, alcohol dependence can be modulated by many factors whose primary target is not the brain,” Rietschel said. “The best known genetic variants modulating alcohol addiction are variants in the genes metabolizing alcohol, like variants in the alcohol dehydrogenase gene clusters.” 7 Indeed, this study confirmed several other SNPs associated with alcohol dependence, including those located in the ADH1C gene coding for one of the alcohol-metabolizing alcohol dehydrogenases, as well as the CDH13 gene coding for a cell-adhesion protein known as T-cadherin. Both genes have been implicated in
① ② ③ ④
Genomewide Association Study 全基因组关联研究 Single Nucleotide Polymorphisms 单核苷酸多态性 abbr. Medicinae Doctor （[拉丁语] 医学博士(=Doctor of Medicine)） Psychiatric News is the newspaper of the American Psychiatric Association (APA). It is published on the first 德国海德堡大学曼海姆中央精神卫生研究所 1
and third Fridays of each month. 《精神病学新闻》
alcohol dependence in previous studies. 8 Despite the strong evidence, these variants and their impact on alcohol dependence need to be replicated by additional studies. “The uncertainty is a problem encountered in many GWA studies: A SNP is found to be associated but is not functional itself, so one cannot be sure if this SNP is itself involved in the regulation of genes or if it is only in LD with other causal SNPs, which can be quite far away or even in other genes,” said Rietschel. Since the three top SNPs discovered in this study are close to and in the PECR gene, “this gene definitely merits further investigation.” 9 The researchers first performed a genomic scan for more than 500,000 SNPs, using a sample of 487 alcohol-dependent patients and 1,358 controls. The GWAS identified 121 SNPs that were likely candidates for genetic association. 10 The patients selected for the GWAS were German men with a DSM-IV diagnosis of alcohol dependence, whose condition was severe enough to require hospitalization for treatment or prevention of alcohol withdrawal. In addition, the subjects all had an onset of alcohol dependence before age 28; early-onset alcohol dependence has been shown to have a stronger hereditary component. Because alcohol dependence is a multifactorial disorder with multiple phenotypes and genotypes, the researchers narrowed their sampling to clinically similar patients to reduce the heterogeneity. 11 Because of the vast number of mutations existing in every person and the large number scanned in a GWAS, scientists face the challenge of weeding out too many potential false-positive “hits,” or variants that appear to be significantly associated with a disease when they are, in fact, random coincidences. To minimize false hits and maximize true disease-associated mutations, strategies such as stringent statistical criteria and replication studies are often used in genetic association studies. 12 Here, the researchers used a method called convergent functional genomics. This approach combines gene-expression data from animal models, evidence from human genetic association studies, and findings from human tissues such as brain tissue in autopsies to help prioritize investigation on the most promising candidate genes or the most likely biological pathways. In this study, 19 SNPs were identified after the human GWAS findings were compared with homologous, over-expressed genes in rats that were “alcoholic” strains. 13 Armed with 121 candidate SNPs from the GWAS and 19 SNPs derived from convergent functional genomics analysis, the researchers performed a replication study of 1,024 male patients with alcohol dependence and 996 age-matched controls. The replication study confirmed that 15 SNPs have a significant association with alcohol dependence. 14 This study was funded by grants from the German government and the European Commission. Source: http://pn.psychiatryonline.org/content/44/16/25.1.full Words: 776
Words and Expressions genomic [? i:'n?? m? k] adj. of or relating to genome 基因组的；染色体的 target gene 目标基因 dependence [d? 'pend?ns] n. being abnormally tolerant to and dependent on something that is psychologically or physically habit-forming（毒） 瘾，吸毒癖好；药瘾 alcohol dependence 酒精瘾 alcohol use disorders 因酒精使用而导致的障碍 nucleotide ['nju:kl? ?ta? d] n. a phosphoric ester of a nucleoside; the basic structural unit of nucleic acids (DNA or RNA) 核苷酸 polymorphism [,p? l? 'm? :f? zm] n. (biology) the existence of two or more forms of individuals within the same animal species (independent of sex differences) 多形性（现象）； 多态性 degree of association 相关度，关联度 disequilibrium [,d? s? kw? 'l? br? ?m] n. loss of equilibrium attributable to an unstable situation in which some forces outweigh others（尤指经济上的）不平衡，失 去平衡，失调，不稳定 linkage disequilibrium 连锁不平衡 express [? ks'pres] vt. manifest the effects of (a gene or genetic trait) 使（某一基因） 在表型中产生有关性状；在表型中表现某一基因的性状（或 效应等），使（基因）示性；使（基因）合成特种蛋白 dehydrogenase [di:'ha? dr?? ?ne? s] n. 脱氢酶 alcohol dehydrogenase 醇脱氢酶 gene cluster 基因簇；一组相同或者相似的基因 adhesion protein 粘着蛋白 cadherin 钙黏蛋白 genomic scan 基因组扫描 hospitalization [,h? sp? t?la? 'ze? ? ?n] n. the condition of being treated as a patient in a hospital; a period of time when you are confined to a hospital 送进医院治疗； （治 住院 疗） ；住院期间 alcohol withdrawal 戒酒；酒精戒断 hereditary [h? 'red? t?r? ] adj. tending to occur among members of a family usually by heredity 遗传的；遗传性的 multifactorial [,m? lt? f?k't? :r? ?l] adj. involving or depending on several factors or causes (especially pertaining to a condition or disease resulting from the interaction of many genes) 多遗传因子的；多种因素的 phenotype ['fi:n?,ta? p] n. what an organism looks like as a consequence of the interaction of its genotype and the environment 表现型；
表型；显型 genotype ['? i:n?? ta? p] n. a group of organisms sharing a specific genetic constitution 基因型，遗传型 heterogeneity [,het?r?? d? ? 'ni? t? ] n. the quality of being diverse and not ? comparable in kind 多样性，不均一性；异质性 false-positive 假阳性的 functional genomics 功能基因组学 homologous [h? 'm? l?g?s] adj. having the same evolutionary origin but serving different functions 同种异体的；相应的，同源的； 同系列的，同属列的，同周期的；（细胞、抗血 清等）同种的
Comprehension Exercises Exercise 1 Multiple Choices Directions: Choose the best answer to each of the following questions. 1) According to GWAS, how many SNPs are found to have the highest degree of association with alcohol dependence? A) One. B) Two. C) Three. D) Four. 2) Which of the following statements is true, according to the text? A) Two single nucleotide polymorphisms (SNPs), both located on the chromosomal region 2p33, had a slightly lower degree of association with alcohol dependence. B) Because of the strong evidence, these SNPs and their impact on alcohol dependence needs no additional studies. C) Because alcohol does not act only on the brain, alcohol dependence can be modulated by many factors whose primary target is not the brain. D) Armed with 121 candidate SNPs from the GWAS and 19 SNPs derived from convergent functional genomics analysis, the researchers performed a replication study of 1358 male patients with alcohol dependence and 487 age-matched controls. 3) Which gene is helpful to further gene studies, according to a new genomewide association study (GWAS)? A) SNPs B) CDH13 C) ADH1C D) PECR 4) Which of the following strategies or methods is not the one adopted in order to minimize false hits and maximize true disease-associated mutations? A) Stringent statistical criteria. B) Replication studies. C) Convergent functional genomics. D) Genomic scan Key: B-C-D-D Exercise 2 True or False Statements Directions: Read the following statements and decide whether they are true (T) or false (F). （ ）1) Genomic association studies can explain disease mechanisms because it helps scientists pick out target genes and biological pathways for
（ （ （ （
）4) ）5) ）6) ）7)
further investigation. A new genomewide association study (GWAS) has found several mutations related to alcohol dependence. SNPs which are located near the PECR gene, encode an enzyme (peroxisomal trans-2-enoyl-coA reductase) involved in fatty-acid metabolism. The three SNPs which are proved to have degree of association with alcohol dependence are near or within the PECR gene. Marcella Rietschel believed that it is very likely that the PECR gene is involved in alcohol dependence. The PECR gene is expressed most heavily in the liver, but very little in the brain. The best known genetic variants modulating alcohol addiction are variants in the genes metabolizing alcohol, like variants in the dehydrogenase gene clusters. ADH1C gene is the gene codes for one of the alcohol-metabolizing alcohol dehydrogenases known as T-cadherin.
Key: F-T-F-T-T; T-F-F Exercise 3 Word-detecting Directions: Find a word in the designated paragraph to complete the sentence. 1) ADH1C gene and CDH13 gene have been i in alcohol dependence in previous studies. (Para. 7) 2) The u is a problem encountered in many GWA studies. (Para. 8) 3) The patients selected for the GWAS were German men with a DSM-IV diagnosis of alcohol d . (Para. 10) 4) Alcohol dependence is a m disorder with multiple phenotypes and genotypes. (Para. 10) Key: 1) implicated 2) uncertainty 3) dependence 4) multifactorial Vocabulary Exercises Enhance your command of medical words Exercise 1 Word-matching Directions: Choose the definitions in the right column to match the words in the left column.
1) 2) 3) 4) 5) 6) 7) 8)
nucleotide polymorphism loci express dehydrogenase cadherin phenotype genotype
a) b) c) d) e) f) g) h)
（基因）座位（locus 的复数） 核苷酸 表现型；表型；显型 多形性（现象）；多态性 使（基因）示性；使（基因）合成特种蛋白 脱氢酶 钙黏蛋白 基因型，遗传型
Key: b-d-a-e-f-g-c-h Exercise 2 Translation Directions: Translate the following terms into Chinese. target genes alcohol dependence use disorders 4) degree of association 5) linkage disequilibrium 6) alcohol dehydrogenase
1) 2) 3)
gene cluster adhesion protein genomic scan 10) alcohol withdrawal 11) false-positive 12) functional genomics
7) 8) 9)
Key: 1) 目标基因 2) 酒精瘾 3) 使用障碍 4) 相关度，关联度 5) 连锁不平衡 6) 醇脱氢酶 7) 基因簇；一组相同或者相似的基因 8) 粘着蛋白 9) 基因组扫描 10) 戒酒；酒精戒断 11) 假阳性的 12) 功能基因组学 Exercise 3 Word-detecting Directions: Find a word in the designated paragraph to complete the sentence. 1) The physician should also order 2) People with diabetes have too much 3) In the absence of an accurate (Para. 10)
and hormonal studies. (Para. 3) , or sugar, in their blood. (Para. 3) , no basis exists for selecting a treatment.
4) Doctor: I can do nothing about your condition. I’m afraid it’s . (Para. 10) 5) The two loci all have sequence . (Para. 10) 6) Translocation occurs when a fragment of one chromosome becomes attached to a nonchromosome. (Para. 12) Key: 1) chromosomal 2) glucose 3) diagnosis 4) hereditary 5) heterogeneity 6) homologous Translation of the sentences 1) 还应该进行染色体和激素水平的检查。 2) 糖尿病患者血液中含有过多的葡萄糖，或称之为糖。 3) 如果缺乏准确的诊断，也就没有为选择治疗方式提供基础。 4) 医生：你的情况我爱莫能助。这应该是遗传所致。 5) 两基因座均存在序列异质性。 6) 一段染色体跟非同源染色体连在一起时就发生易位。 Enhance your command of general words Exercise 1 Blank-filling Directions: Choose words from the box to complete the sentences. Change the word form when necessary. minimize identify encode encounter additional multifactorial random convergent weed out strategy maximize compare…with switch from…to… stringent candidate combine…with…
1) Once these are discovered, the proteins they (genes) can be added to the lists of those that are targets for the molecular medicinal drug-makers. 2) Note how quickly countries exporting importing labour as they develop. 3) The supplies due to this policy lower the world price of sugar. 4) Here, you will all or cute, or a little monster of terror. 5) Environmental quality assessment is a assessment. 6) The police are the unlicensed pedler. 7) The mistakes that are identified are not , but systematic. 8) Government officials the importance of the film. 9) We’re also going to rearrange the furniture to the use of space. 10) First you assess the facts on the ground, then you present a new . 11) People began verify their scientific hypotheses by tests.
12) Info-tech can arouse student’s interest in study, induce the conscious of creation, practise divergent thinking and thinking. 13) It is an essential principle that we must theory practice. 14) The defeated demanded a recount of the votes. 15) Never wealth with happiness. 16) Few other teas can ours either for flavour or colour. Key: 1) encode 2) switch from; to 3) additional 4) encounter 5) multifactorial 6) weeding out 7) random 8) minimize 9) maximize 10) strategy 11) stringent 12) convergent 13) combine; with 14) candidate 15) Identify 16) compare with Translation of the sentences 1) 一旦这些基因被我们发现，它们所分解出的蛋白就能被很好地定位并为分子 药品制造商在药物制造中所利用。 2) 随着各国的发展， 请注意这些劳工输出国转向劳工进口国的速度是何等迅速。 3) 因这一政策的出台而增加了供给，继而压低了食糖的国际价格。 4) 在这里，你将遇到各种各样或可爱，或恐怖的小小怪兽。 5) 环境质量评价是一种多因素的评价。 6) 警察正在取缔无证商贩。 7) 这种已被确认的错误并非随机出现，而是成系统的。 8) 政府官员尽量弱化这部电影的影响。 9) 我们还想重新布置一下客厅的家具来得到最大的可用空间。 10) 首先，你要对事实进行实地评估，然后才提出一项新的策略。 11) 人们开始用精确的试验证实自己的科学假说。 12) 信息技术可以激发学习兴趣，诱发创造意识，锻炼发散性思维和集中性思维。 13) 我们必须把理论与实践相结合是个重要的原则。 14) 被击败的候选人要求重新计算选票。 15) 千万不要把财富等同于幸福。 16) 在香味或色泽方面，其它牌号的红茶很难与我们的红茶相比。
Sentence Translation Directions: Translate the following sentences from the text into Chinese. 1) A new genomewide association study (GWAS) has found several mutations linked to increased susceptibility for developing alcohol dependence, bringing scientists a step closer to understanding the complex biological mechanisms of alcohol use disorders. 2) Two single nucleotide polymorphisms (SNPs), both located on the chromosomal region 2p35, had the highest degree of association with alcohol dependence in a relatively homogenous patient population. 3) These SNPs are located near the PECR gene, which encodes an enzyme (peroxisomal trans-2-enoyl-coA reductase) involved in fatty-acid metabolism, particularly when the body’s energy supply is switched from glucose to fat. 4) Indeed, this study confirmed several other SNPs associated with alcohol dependence, including those located in the ADH1C gene coding for one of the alcohol-metabolizing alcohol dehydrogenases, as well as the CDH13 gene coding for a cell-adhesion protein known as T-cadherin. 5) The researchers first performed a genomic scan for more than 500,000 SNPs, using a sample of 487 alcohol-dependent patients and 1,358 controls. The GWAS identified 121 SNPs that were likely candidates for genetic association. 6) Because alcohol dependence is a multifactorial disorder with multiple phenotypes and genotypes, the researchers narrowed their sampling to clinically similar patients to reduce the heterogeneity. Key: 1) 一个新的基因组范围的关联性研究（GWAS）发现几个连锁突变能增加进行 性酒精依赖的敏感性，这带给科学家一个进一步了解酗酒的发杂生物学机理 的方法。 2) 两个都位于染色体上 2P35 区域的单核苷酸多态性（SNPs）对于在相关的同 种疾病总数的酒精依赖上有着最高程度的相关性。 3) 这些单核苷酸多态性位于 PECR 基因附近，PECR 基因是给一种在脂肪酸代 谢中特别是当生物体的能量供给由葡萄糖转化为脂肪时相关的酶（反-2-烯醇 基-辅酶 A 还原酶）编码的。 4) 这项研究证实了若干其他与酒精依赖症的关联的单核苷酸多态性，包括那些 位于 ADH1 基因上，对酒精代谢的乙醇脱氢酶中的一个酶编码的 SNPs 和 CDH13 基因上，对细胞黏附蛋白（T-钙粘蛋白）编码的 SNPs。 5) 研究者使用的是一份 487 名酒精依赖症患者和 1,358 名对照者的样本，首先 完成了多于 500,000 个 SNPs 的基因组扫描。 GWAS 确定了 121 个遗传相关性 的候选 SNPs。 6) 因为酒精依赖症是多种基因型和表现性的多因子病，研究者为减少不均一性 缩小了对临床相似病人的抽样。