《医学遗传学》Medical Genetics

张咸宁E-mail: zhangxianning@zju.edu.cn Tel ： 13105819271; 88208367 Office: A709, Research Building

2011/02

• Nussbaum RL, et al. 张咸宁 , 等 . Thompson & Thompson Genetics in Medicine, 7th ed. （双语版）北京大学医学出版社 , 2009.

Suggested Readings• Turnpenny P, Ellard S. Emery's elements of medical

genetics: With Student Consult Access. 13th edition. Churchill Livingstone, 2007

• Jorde LB, et al. Medical genetics. 4th ed. Mosby, 2010.• Passarge E. Color atlas of genetics.3rd ed. Thieme

Medical Publishers, 2007 • Scriver CR, et al. The metabolic and molecular bases of

inherited disease.8th ed. McGraw-Hill Companies, 2001• Rimoin DL , et al. Emery and Rimoin's Principles and

Practice of Medical Genetics. 5th ed. Churchill Livingstone, 2006

• Berg P, Singer M. Dealing with Genes: The Language of Heredity. University Science Books, 2008

Medicine without biology does not make sense!

----Scriver CR, et al. The metabolic and molecular bases of

inherited disease.8th ed. McGraw-Hill Companies,2001

McKusick VA ：“ In essence, MM is genetic medicine” （ From Runge MS, et al. Principles of molecular medicine. 2nd ed. Humana Press, 200

6 ）

Useful Internet• Information on any mendelian phenotype:

www.ncbi.nlm.nih.gov/omim/• Genome data: www.ensembl.org; http://genome.cse.ucsc.edu• Information on proteins: http://ca.expasy.org• Biomedical literature:

www.ncbi.nlm.nih.gov/entrez/• Human gene mutation database: www.hgmd.org• Human disease genes list:

http://bioinfo.weizmann.ac.il/cards• Genetic diagnosis: www.genetests.org

1966: 《 MIM 》（ McKusick VA, 1921-2008 ）

http://www.ncbi.nlm.nih.gov/omim

Father of Medical Genetics

Last updated:2010/11/10. Numbers of reference: 75. Pubmed search references: 67229 ! (2011/02/09)

Top Journals of Molecular MedicineTop Journals of Molecular Medicine• CNS • NEJM• Lancet• Nature Medicine• Nature Genetics• AJHG• AJMG• Nat. Rev. Genet.• Annu. Rev. Genomics Hum. Genet.• Annu. Rev. Genet.• Trends Mol Med• Genome Res.• Hum. Mol. Genet.• Hum. Mutat. • J. Med. Genet.• Genetics in Medicine

第一章 基因、基因突变– 遗传医学的任务和范畴– 基因、人类基因组、人类基因组计划

（ HGP ）、 OMIM

– 基因突变

Genetic Medicine

• 遗传（ heredity ）：性状在亲代与子代之间的相似性和连续性。

• 人类疾病是细胞病变的综合反映，而细胞病变则是细胞在致病因素的作用下，组成细胞的若干分子相互作用的结果 →除了烧伤、烫伤、食物中毒、营养不良和车祸等以外，所有人类的疾病发生都与基因的直接和间接变化相关。

From Genotype to Phenotype

DNA (genes) Cells Tissues & Organs

OrganismPopulation

Variation （变异）： The differences of individuals resulted from genetic recombination, environmental

modification and genetic mutation.

Genetic (Genomic) Medicine

• The science deals with the subset of human genetic variation that is of significance in the practice of medicine and in medical research.

Any disease is the result of the combined action of genes and environment

Classification of genetic disorders:1. Chromosome disorders:2. Single-gene disorders:3. Complex (multifactorial,

polygenic) disorders:4. Somatic cell genetic disorders:5. Mitochondrial genetic disorders:

第一章 基因、基因突变– 遗传医学的任务和范畴– 基因、人类基因组、人类基因组计划

（ HGP ）、 OMIM

– 基因突变

Gene/ Genome

• Gene: A hereditary unit; a sequence of chromosomal DNA that is required for the production of a functional product.

• Genome: The complete DNA sequence, containing the entire genetic information, of a gamete, an individual, a population, or a species.

• Genomics: The field of genetics concerned with structural and functional studies of the genome.

持家基因 / 奢侈基因• Housekeeping gene : Genes which express

proteins common to all cells, e.g. ribosomal, chromosomal and cytoskeletal proteins.(β-actin, GADPH) 几乎在一切体细胞中均能被表达的基因

• Luxury gene: are those coding for specialized functions synthesized (usually) in large amounts in particular cell types. 特异表达的基因

等位基因 / 基因型 / 表型• Allele: One of the different forms of a

gene pair. At each autosomal locus an individual possessed two alleles, one inherited from mum and one from dad.

• Genotype: The combination of alleles that an individual possesses.

• Phenotype: The physical characteristics of a cell or organism as defined by its genetic constitution.

A A

BB

a

b b

a A A

BB

a

b b

a

CD

CD

cd

cd

cd

CD

CD

cd

A pair of homologous chromosomespairing at meiosis

Cross over occursbetween the genes - most likely when genes are far apart.

Segregation

Recombinant chromatidsParentalchromatids

Parentalchromatids

Segregation

Cross over and recombinationis rare since genes are very close together.

Genetic Recombination - The mixing of gene combinations

Gene Structure ： split gene 割裂基因

Nomenclature of genes & proteins ！• http://www.gene.ucl.ac.uk/nomenclature/

index.html• Antonarakis SE.  (1998) Recommendations

for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 11:1-3.

• den Dunnen JT, Antonarakis SE. (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion. Hum Mutat. 15:7-12.

General organization of human genome

20000-25000

β-globin gene

Human Genome Project, HGP• Began from 1990 in USA, UK, France, Japan, to sequence total 3 billion base pair in 100 000

genes of a haploid set of human genome in 15 years (Watson JD) (Collins F)

HGP: the first draft, 2001

International Human Genome Sequencing Consortium.Nature,2004,431:931-945

世界首张个人基因组图（世界首张个人基因组图（ James James WatsonWatson ）） 20072007 年年 55 月月 3030 日公布日公布

心脑血管基因

肿瘤抑制基因

天分基因 药物毒物代谢基因

老年痴呆基因

第一章 基因、基因突变– 遗传医学的任务和范畴– 基因、人类基因组、人类基因组计划

（ HGP ）、 OMIM

– 基因突变 (gene mutation)

Polymorphism 多态性

• Occurrence of at least two alleles at a locus each having a frequency of at least 1%.

指同一群体中存在有 2 种或以上可变基因型的现象，每种类型的比例应大于 1﹪ 。

SNP （单核苷酸多态性） : A change in which a single base in the DNA differs from the usual base at that position. SNPs are the most common type of variations. Millions of SNP's have been cataloged in the human genome. Some SNPs such that which causes sickle cell are responsible for disease. Other SNPs are normal variations in the genome.

基因突变分为两大类：静态突变 (static mutation) 和动态突变 (dynamic

mutation)

Mutations • Mutations change the sequence of DNA:

spontaneous and induced

• Point mutation, deletion, insertion

• Frameshift, truncation, exon skipping

• Hotspots

HbS -CCT GTG GAG--Pro Val Glu-

HbA -CCT GAG GAG--Pro Glu Glu-

Sickle cellSickle cellanemiaanemia

点突变（ point mutation ）

• DNA 链中一个或一对碱基发生的改变，两种形式：碱基置换和移码突变。

转换（ transition ） : 一种嘌呤 - 嘧啶对被另一种嘌呤 - 嘧啶对所替换。

颠换（ transvertion ） : 一种嘌呤 - 嘧啶对被另

一种嘧啶 - 嘌呤对所替换 。

• 同义突变（ same sense mutation ） 碱基被替换之后，产生了新的密码子，但新旧密

码子同义，所编码的氨基酸种类保持不变，因此同义突变并不产生突变效应 。

•无义突变（ non-sense mutation ） 碱基替换使编码氨基酸的密码变成终止密码

UAA 、 UAG 或 UGA 。

•错义突变（ missense mutation ） 碱基替换使编码某种氨基酸的密码子变成编码

另一种氨基酸的密码子，从而使多肽链的氨基酸种类和序列发生改变。

•终止密码突变（ terminator codon mutation）

DNA 分子中的某一个终止密码突变为编码氨基酸的密码，从而使多肽链的合成至此仍继续下去，直至下一个终止密码为止，形成超长的异常多肽链。

•影响非密码子区域的突变

调控序列突变：使蛋白质合成的速度或效率发生改变，进而影响着这些蛋白质的功能，并引起疾病。

内含子与外显子剪辑位点突变： GT-AG 中的任一碱基发生置换而导致剪辑和加工异常，不能形成正确的 mRNA 分子。

移码突变（ frame-shift mutation ）

基因组 DNA 链中插入或缺失 1 个或几个碱基对，从而使自插入或缺失的那一点以下的三联体密码的组合发生改变，进而使其编码的氨基酸种类和序列发生变化。

Dynamic mutation

• 某些单基因遗传病是由于脱氧三核苷酸串联重复扩增（ trinucleotide repeat amplification ）所引起的，而且这种串联重复的拷贝数可随世代的递增而呈现累加效应，故称这种突变方式为动态突变。

• 脆性 X 综合征 Xq27.3 内 (CGG)n 重复数： 60-200 ，正常： 6-6

0

脆性 X 综合征患者：智力低下，皮肤松弛，关节过度伸展，长脸。

Locations of Repeats

Richards & Sutherland, TIBS, 22(1997)432.Richards & Sutherland, TIBS, 22(1997)432.Richards & Sutherland.TIBS,1997;22:432.

表观遗传学（ epigenetics ）

• 在基因的核苷酸序列不发生突变的情况下，基因的修饰如 DNA甲基化、组蛋白的乙酰化等也可能导致基因的活性发生改变，使基因决定的表型出现变化，且可传递少数世代。