Genetic Linkage And Pedigree Analysis Lecture PDF

Republic of Iraq Ministry of Higher Education and Stage:S2 Scientific Research Module: MGD Wasit Universty College of medicine :Lecture Title Genetic linkage and Pedigre...

Republic of Iraq Ministry of Higher Education and Stage:S2 Scientific Research Module: MGD Wasit Universty College of medicine :Lecture Title Genetic linkage and Pedigree analysis Lecturer Name: Dr –Dhamyaa K. Kadhim Inheritance (heredity): is a process of transmission of characters from generation to next (parents to children). Genetics: is the study of genes and of the statistical laws that govern the passage of genes from generation to next 2 One individual has(heredity): Inheritance two alleles of any is agiven gene locus process on homologous of of transmission chromosomes. characters from Homozygous: Both alleles of a gene are the same Heterozygous: Two generation toofnext different alleles (parents a gene to children). Hemizygous: Only one allele of a gene represent in the genes on X chromosome in male Mendel's first law: The principle of segregation Genetics: is the study of genes and of the statistical laws that govern the Mendel's second law: passage The of genesoffrom principle generation independent to next assortment 3  Pedigree construction is an important tool in human genetics Pedigree construction: is the fundamental method of genetic analysis in humans using family history to determine how a trait is inherited and to estimate risk factors for family members. Pedigree A diagram listing the members and ancestral relationships in a family; used in the study of human heredity: ►the inheritance of a trait can be followed through several generations. ►Analysis of the pedigree using the principles of Mendelian inheritance can determine whether a trait has a dominant or recessive pattern of inheritance. 4  Pedigree construction is an important tool in human genetics ►Pedigrees use a standardized set of symbols, some of which are shown in following figure: 5  Pedigree construction is an important tool in human genetics ►A numbering system is used in pedigree construction. Each generation is identified by a Roman numeral (I, II, III, and so on), and each individual within a generation is identified by an Arabic number (1, 2, 3, and so on): ►Pedigrees are oft en constructed after a family member afflicted with a genetic disorder has been identified. The is individual, known as the proband, is indicated on the pedigree by an arrow and the letter P:  Pedigree analysis is a basic method in human genetics Analysis of pedigrees using knowledge of Mendelian principles has two initial goals: To determine whether the trait has a dominant or a recessive pattern of inheritance. To discover whether the gene in question is located on an X or a Y chromosome or on an autosome (chromosomes 1 to 22). If the pattern of inheritance can be established, it can be used to predict genetic risk in several situations, including: ✔ Pregnancy outcomes ✔ Adult-onset disorders ✔ Recurrence risks in future off spring The collection, storage, and analysis of pedigree information can be done manually or by using software  Mendelian inheritance patterns (single gene disorders) Mendelian patterns of inheritance for traits controlled by single genes can be classified into five basic patterns, according to the whether gene responsible to genetic disorder resides on an autosome or a sex chromosome, and also whether that gene is expressed in its homozygous or heterozygous state, which are autosomal recessive inheritance autosomal dominant inheritance X-linked recessive inheritance X-linked dominant inheritance Y-linked 8 inheritance  Mendelian inheritance patterns (single gene disorders) 1-Autosomal Recessive Inheritance (AR) It is result from defect gene located on an autosome and expressed in homozygous state, having several distinguishing characteristics: Heterozygotes unaffected while homozygotes affected Mating between two heterozygotes individuals having: - risk of affected child = 25% - phenotypically unaffected carrier child= 50% - normal child = 25 % Two affected (homozygous) individuals having: - all offspring usually affected Males and females are at equal risk Affected individual usually in one single generation 9 Consanguineous marriage play important role in appear of this disorder 1-Autosomal Recessive (AR) Assume normal allele= A Assume mutant allele= a 10 Genotype and Recurrence risk 1-Autosomal Recessive (AR) Assume normal allele= A Assume mutant allele= a Genotype and Recurrence risk 1-Autosomal Recessive (AR) A pedigree illustrating a pattern of inheritance typical of autosomal recessive genes is shown in the following figure: A diagram shown below illustrating a autosomal recessive pattern: 12 1-Autosomal Recessive (AR) A number of autosomal recessive genetic disorders are listed in the following table: 13  Mendelian inheritance patterns (single gene disorders) 2-Autosomal Dominant Inheritance (AD) It is result from defect gene located on an autosome and expressed in heterozygous state, having several distinguishing characteristics: Heterozygotes affected Very rare that found in homozygous state Affected person (Heterozygote) has 50% chance of transmitting the trait Males and females are at equal risk Every affected individual usually has an affected parent, meaning the disease seen in every generation 14 2-Autosomal Dominant(AD) Assume normal allele= a Assume mutant allele= A Genotype and Recurrence risk 15 2-Autosomal Dominant (AD) A pedigree illustrating a pattern of inheritance typical of autosomal dominant genes is shown in the following figure: A diagram shown below illustrating a autosomal dominant pattern: 16 2-Autosomal Dominant (AD) A number of autosomal dominant genetic disorders are listed in the following table: 17  Co-dominance Co-dominant alleles are fully expressed in heterozygotes. Example is ABO blood types: ❖ Isoglutamin gene (I) codes for proteins (glycoproteins) on the surface of red blood cells. ❖ There are three alleles, IA, IB, and i. ❖ ABO blood types as follows:  Mendelian inheritance patterns (single gene disorders) 3-X-linked Recessive Inheritance (XLR) It is result from defect gene located on X chromosome and expressed in homozygous state, having several distinguishing characteristics: Only Hemizygous males usually affected Transmitted through unaffected carrier females - risk of affected son= 25% (50% of males) - normal son = 25 % (50% of males) -unaffected carrier daughter= 25% (50% of females) - normal daughter = 25 % (50% of females) Affected males transmit the disorder to daughters (all be carriers 100%) but not to sons (100% normal) 3-X-Linked Recessive (XLR) Assume normal allele= A / XA Assume mutant allele= a/ Xa 20 Genotype and Recurrence risk 3-X-linked Recessive (XLR) A pedigree illustrating a pattern of X-linked recessive inheritance is shown in the following figure: 3-X-linked Recessive (XLR) A number of X-linked recessive genetic disorders are listed in the following table: 22  Mendelian inheritance patterns (single gene disorders) 4-X-linked Dominant Inheritance (XLD) It is result from defect gene located on X chromosome and expressed in heterozygous state, having several distinguishing characteristics: Males and females affected Females less severely affected than males Affected males can transmit the disorder to all their daughter (all be affected 100%), but not to sons (100% normal) Affected females have a 50% affected children, irrespective of sex. On average, twice as many females are affected as males (females can be heterozygous or homozygous). 4-X-linked Dominant (XLD) A pedigree illustrating a pattern of X-linked dominant inheritance is shown in the following figure: Examples: X-linked dominant retinitis pigmentosa, Rett syndrome, and Hypophosphatemia  Mendelian inheritance patterns (single gene disorders) 5- Y-linked inheritance It is rare and result from defect gene located on Y chromosome and is inherited directly from father to son. Only males are affected. Affected males must transmit a disorder to their sons who are also be affected as shown in a pedigree below: Examples: Infertility and Hairy pinna Complementation More than one gene can be involved in producing a phenotype Substrate Enzyme 1 Gene 1 Intermediate 1 Enzyme 2 Gene 2 Intermediate 2 Enzyme 3 Gene 3 Product  Linkage ✔ Genes on the same chromosome said to be linked , when these genes are close together. ✔ Linked genes do not show independent assortment at meiosis but tend to be inherited together ✔ The frequency of recombination between linked genes gives an indication of distance between them 27 28  Genetic Map ✔ Arrangement and distance between genes on a chromosome deduced from studies of recombination: 1 map unit = 1% recombination Map unit or centimorgan (cM): is a measure of the genetic (or linkage) distance between two loci If two loci are 1 cM apart, a crossover occurs between them on average only once in every 100 meiosis. ✔ Mapping more accurate when genes are close together  THANK YOU 30