复旦大学：《医学遗传学 Medical Genetics》课程教学资源（PPT课件讲稿）Single Gene Disorders

Medical genetics Single gene Disorders Lecturer: david saffen Ph. D Laboratory for Molecular Neuropsychiatric Genetics Department of Cellular and Genetic Medicine School of Medicine, Fudan University saffen@fudan.edu.cn

Medical Genetics: Single Gene Disorders Lecturer: David Saffen. Ph.D. Laboratory for Molecular Neuropsychiatric Genetics Department of Cellular and Genetic Medicine School of Medicine, Fudan University saffen@fudan.edu.cn

Outline A Historical Background B. Patterns of inheritance C. Genetic mutations D. Prenatal diagnosis

Outline A. Historical Background B. Patterns of inheritance C. Genetic mutations D. Prenatal diagnosis

A. Historical Background Gregor Mendel Archibald garrod Thomas Hunt Morgan Linus Pauling

A. Historical Background • Gregor Mendel • Archibald Garrod • Thomas Hunt Morgan • Linus Pauling

Gregor Mendel Established the rules of inheritance of discrete traits in plants, providing the foundation for the discovery of the gene and the establishment of the modern science of genetics Mendels laws Law of Segregation Each individual possesses two factors(alleles)for a given trait, which "segregate"during the formation of gametes in such a manner that each gamete contains only one of the factors(alleles). Progeny subsequently receive one factor (allele) from their father and one factor (allele) from their mother 1822-1884; German-speaking Law of Independent Assortment Augustinian friar in Brno, silesia Factors(alleles) for distinct traits are inherited (currently Czech Republic) independently, i.e. the inheritance of a factor(allele)for one trait does not influence the inheritance of a factor (allele)for a second trait

Gregor Mendel 1822-1884; German-speaking Augustinian friar in Brno, Silesia (currently Czech Republic) Established the rules of inheritance of discrete traits in plants, providing the foundation for the discovery of the gene and the establishment of the modern science of genetics Mendel’s Laws: Law of Segregation: Each individual possesses two factors (alleles) for a given trait, which “segregate” during the formation of gametes in such a manner that each gamete contains only one of the factors (alleles). Progeny subsequently receive one factor (allele) from their father and one factor (allele) from their mother Law of Independent Assortment: Factors (alleles) for distinct traits are inherited independently, i.e. the inheritance of a factor (allele) for one trait does not Influence the inheritance of a factor (allele) for a second trait

Archibald garrod Postulated that recessive metabolic disorders resulted fror the inheritance of a defective enzyme from each parent Garrods tetrad: alkaptonuria, cystinuria pentosuria, albinism Phenylalanine Tyros p-Hydrowylphenylpyruwc acid ogenic acd Urine samples from patient +× Homogentsic acid ox 1857-1936 British physician with alkaptonuria. Left (freshly Professor Oxford University voided); right (after 24 h at RT) Maleylacetoacetc acid Published Inborn Errors of Metabolism" in 1908 OH HO OH Cystine stone in the urinary bladder OH O Xylulose accumulates in the urine Cystinuria (caused by defects in the SLC3A1 of patients with pentosuria. and SLC7A9 transporter genes) (caused by L-xylulase deficiency) Albinism (caused by a deficiency of tyrosinase, a enzyme required for the synthesis of melanin)

Archibald Garrod 1857- 1936; British physician Professor Oxford University; Published Inborn Errors of Metabolism” in 1908 Postulated that recessive metabolic disorders resulted from the inheritance of a defective enzyme from each parent. Garrod’s tetrad: alkaptonuria, cystinuria, pentosuria, albinism Urine samples from patient with alkaptonuria. Left (freshly voided); right (after 24 h at RT) Albinism (caused by a deficiency of tyrosinase, a enzyme required for the synthesis of melanin) Cystinuria (caused by defects in the SLC3A1 and SLC7A9 transporter genes) Xylulose accumulates in the urine of patients with pentosuria. (caused by L-xylulase deficiency)

Thomas Hunt Morgan Working with Drosophila, established that gene are carried on chromosome and form the functional basis of heredity: essentially establishing the modern science of genetics X X 1866-1945: American Geneticist Professor Columbia and california Institute of Technology; Tan Jiazhen Nobel Prize: Physiology or Medicine 1933 Link with (谈家桢) Fudan “ Father of modern University genetics in China 1909-2008

Thomas Hunt Morgan Link with Fudan University: 1866- 1945; American Geneticist Professor Columbia and California Institute of Technology; Nobel Prize: Physiology or Medicine 1933 Working with Drosophila, established that gene are carried on chromosome and form the functional basis of heredity: essentially establishing the modern science of genetics Tan Jiazhen (谈家桢) “Father of modern genetics in China” 1909-2008

x为了帮助保护您的隐私, PowerPoint己阻止自动下载此图片 Linus Pauling First to demonstrate of the molecular basis of a genetic disease, sickle cell anemia: essentially establishing the field of molecular genetics Sickle-like appearance of red blood cell isolated from sickle cell anemia patient (left) compared to normal red blood cell (right). 1901-1994: American quantum a) Normal c)Sickle Cell Trait chemist and biochemist Professorat the california Institute of Technology Stanford University Nobel Prizes: Chemistry 1954: Peace 1962: Published: b)Sickle Cell Anemia d)50-50 Mixture of a)and b) Itano l et al, "Sickle Cell Anemia, a Molecular Disease' o Electrophoresis of Co-hemoglobin isolated from Science110,1488-1490,1949 rmal Individual (a)or individuals heterozygous(b)or homozygous(c) for hemoglobin mutation

Linus Pauling First to demonstrate of the molecular basis of a genetic disease, sickle cell anemia: essentially establishing the field of molecular genetics 1901-1994; American quantum chemist and biochemist. Professor at the California Institute of Technology & Stanford University Nobel Prizes: Chemistry 1954; Peace 1962; Published: Itano I et al, “Sickle Cell Anemia, a Molecular Disease” Electrophoresis of CO Science110, 1488-1490, 1949 -hemoglobin isolated from normal Individual (a) or individuals heterozygous (b) or homozygous (c) for hemoglobin mutation. Sickle-like appearance of red blood cell isolated from sickle cell anemia patient (left) compared to normal red blood cell (right)

B. Patterns of inheritance within pedigrees Autosomal dominant Penetrance and expressivity Autosomal recessive Consanguinity and inbreeding Co-dominant Incompletely dominant X-inked dominant X-linked recessive Y-linked

B. Patterns of inheritance within pedigrees Autosomal dominant Penetrance and expressivity Autosomal recessive Consanguinity and inbreeding Co-dominant Incompletely dominant X-linked dominant X-linked recessive Y-linked

or union Probands Female ○ Consanguinity and Number of children of sex indicated Monozygotic twins 口 AFfected pedigrees ① Nonpenetrant camer, y manifest disease 口 ○ Dizygotic twin Twins of unknown zygosity Proband and individuals Deceased individual 人 Adopted into family d Adopted out of family Multiple unions Arrow indicates seeking counseling 岛 dates if available 人人

Probands and pedigrees

Punnett squares Sperm Sperm Genotype combination A-allele a-allele of alleles at a specific locus ggs AA aA A-allele Eggs aa a-allele Sperm Sperm A-allele a-allele Eggs AA aA unaffected A= normal(major) allele A-allele a= mutated(minor)allele ggs aa affected a-allele

Sperm A-allele Sperm a-allele Eggs A-allele AA aA Eggs a-allele Aa aa “Punnett squares” Sperm A-allele Sperm a-allele Eggs A-allele AA aA Eggs a-allele Aa aa A = normal (major) allele a = mutated (minor) allele affected A a Genotype = combination of alleles at a specific locus unaffected