Biol139-lecture4-201 - BIOL 139 BIOL Pedigree Analysis Pedigree Chapter 2 con’t some of Chapter 3 Chapter pp 30 33 66 69 iGenetics pp 30 35

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Unformatted text preview: BIOL 139 BIOL Pedigree Analysis Pedigree Chapter 2 con’t (+ some of Chapter 3) Chapter pp 30 - 33, 66 - 69 iGenetics pp 30 - 35 H (tutorial 3) (tutorial Disadvantages to Genetic Studies in Humans: Disadvantages • • • generation time is long generation few offspring few no pure-breeding lines or controlled matings no • no true F2-generation; no interbreeding of no -generation; families families • Geneticists can follow a phenotype in: Geneticists • large families large • generations of same family generations • this family history known as a pedigree this Pedigree Analysis Pedigree Many human traits run in families : most do not show a simple Mendelian pattern of inheritance show Why ? Because most are influenced by more than one gene -multifactorial i.e. eye colour one Most confirmed single-gene traits in people are relatively rare, involving abnormalities that are either disabling or life-threatening Studying family genetic histories, or pedigrees, gives insight as to how mutant alleles causing abnormalities are inherited abnormalities Examples of single-gene traits in humans Examples Thalassemia pg 31, 301-302,337 Abnormal or reduced levels of hemoglobin, anemia, bone and spleen enlargement Sickle–cell disease Abnormal hemoglobin, sickle-shaped red cells, pg 31, 55, 337 anemia, blocked circulation, increased resistance to malaria Tay-Sachs disease Missing enzyme; build-up of fatty deposit in brain; pg 31, 54 build-up destroys nervous development; blindness, paralysis, mental retardation Phenylketonuria (PKU) Mutation in enzyme in metabolic pathway pg 31, 67 causes the amino acid phenylalanine to build up. Body deals with this by converting it to phenylpyruvic acid which interferes with early development of the nervous system; mental deficiency in untreated young β -thalassemia Hemoglobin is a tetrameric protein, made of 2 subunits of α-globin and 2 subunits of β -globin -in β -thalassemia, a mutation just in front of the coding region for the β -globin chain results in non-production of this subunit. Examples of single-gene traits in humans Examples Albinism Albinism pg 63-64 Missing enzyme in pathway to melanin production; unpigmented skin, hair and eyes Hypercholesterolemia Missing protein that removes cholesterol from Hypercholesterolemia pg 31 the blood: early heart attacks Huntington disease Progressive mental and neurological damage; pg 379 neurologic disorders by ages 40-70. Mutation caused by extra nucleotide repeats in the gene. Not sure what this gene does. Cystic fibrosis Mutations in a protein responsible for chloride ion pg 21, 137 regulation; accumulation of thick mucus in the lungs, digestive organs; difficulty breathing, pneumonia, digestive malfunctions albinism Symbols used in pedigree analysis Symbols Proband propositus - the first person to be investigated in a pedigree -usually the first person to come to the attention of the medical officer General Characteristics of Rare Recessive Traits: General Rare Horizontal pattern of inheritance • most affected individuals have two normal parents, affected both of whom are heterozygous. heterozygous • Trait appears in the next generation since 1/4 Trait of progeny are expected to be homozygous for of recessive allele (Mendel’s pattern of inheritance) recessive • All the offspring of two affected individuals will be All affected affected • Both genders are affected equally Both •most affected individuals have two normal parents, who are heterozygous most heterozygous •trait will appear in roughly ¼ of progeny of heterozygous union • not gender specific not • All the offspring of two affected individuals will be affected All • if trait very rare in population, then parents of affected individuals most often relatives Genotype unknown since too few progeny, but if rare can assume AA (but not always the case) Aa One of these persons is heterozygous Half progeny should be carriers Possibilities: as outlined above which makes most sense since we have two carriers by Generation III. Possible that I-1 is the carrier and I-2 is normal, but probability is that one of these individuals was a carrier.. If not then all of II would be normal and since III 5 and 6 are both carriers from two different “family lines” the trait would need to be introduced in generation II. This would require that II-1 AND II-5 were both carriers of which the probability would be very low especially if rare recessive… again not impossible but not as likely! Albinism: do not produce Albinism: pigment melanin pigment Individuals homozygous for Individuals recessive mutant alleles recessive usually rare • US about 1/17,000 (whites) •1/28,000 in African American • 1/10,000 Irish AA Aa Aa Aa Aa If rare, person expressing trait likely to mate with homozygous normal (AA) Next generation all carriers -“skips” generation -sporadic depending on mate being homo or heterozygote Cystic Fibrosis: Cystic Among Caucasians, about 3% of population are heterozygous heterozygous carriers of the recessive allele carriers abnormalities of pancreas, intestine, sweat glands and lungs abnormalities • imbalance of ions across cell membrane imbalance • in lungs leads to buildup of thick dry mucous in • respiratory problems may lead to early death respiratory Pedigree of a recessive trait Tracking back through generations….. We know that since female 4 has the trait, both parents are carriers From here, it is difficult to track, since there are so few offspring. Assuming it was present in the first generation In generation 1, at least 1 parent is heterozygous. There are not enough Cystic fibrosis children to set the geno-type of the other Cystic fibrosis parent. Summary of Pedigree: Recessive Summary • family pattern of people showing trait is horizontal horizontal • parents, grandparents etc do not themselves manifest disease, but several offspring in one generation may disease, • strong indicator trait is recessive strong • parents are heterozygous carriers carriers • many afflicted children from blood relative couples (1/4) many Sporadic, if affected individual mates with homozygous dominant (if rare) then many generations of phenotypically unaffected progeny will result (sporadic, skips generations –due to all progeny being carriers) Harmful recessive alleles exist in population in higher numbers than harmful dominants since heterozygotes can exist as carriers without any General Characteristics of Rare Recessive Traits: Rare Horizontal pattern of inheritance Affected phenotype only occurs in the homozygous condition (aa) Let A = dominant allele Let a = recessive allele • Most affected children have normal parents (both of whom are Aa) • Heterozygotes (Aa) have normal phenotype • Two affected parents will always have affected children • Close relatives who reproduce are more likely to have affected children • Both males and females are affected equally • Trait will appear in ¼ of progeny of heterozygous union •Horizontal pattern is strong indicator trait is recessive • parents are heterozygous carriers carriers General Characteristics of Dominant Traits: General In many cases, genotypic interactions between two alleles at a locus can be described as dominant or recessive, according to which of the two homozygous genotype (parents) the phenotype of the heterozygote most resembles. Where the heterozygote is indistinguishable from one of the homozygotes the allele is said to be dominant to the other which is said to be recessive The term “wild type” allele is sometimes used to describe an allele that is thought to contribute to the typical phenotypic character as seen in “wild” populations of organisms Such a “wild type” allele was historically regarded as common and “normal” in contrast to “mutant” alleles which are regarded as rare and deleterious General Characteristics of Dominant Traits: General • normal allele is recessive normal • abnormal allele is dominant Terms of phenotype • Dominant mutant alleles are expressed in a heterozygote when they are in combination with heterozygote the wild-type allele + wild-type • wild-type allele is the allele that predominates wild-type (is present in highest frequency) in population (is found in the “wild” found Recessive vs Dominant Alleles chromosome + A mutation Gene for melanin production + wild type allele –makes melanin - Gene for melanin production - mutant allele –no melanin a + Gene for melanin production + wild type allele makes melanin –found most common in nature (population) Remember: Looking at single genes with alternate alleles! Homozygous for trait – which is recessive No production melanin Progeny are albino - - - Aa progeny Heterozygous for trait + wild type allele –makes melanin F1 have colour –resemble one of parents ∴ allele is dominant to – which is recessive + aa Remember: The determination of dominance and recessiveness does not imply anything about the functioning of the alleles - Recessive vs Dominant Alleles chromosome HD+ Gene for Huntingtin -mutant allele altered function -Disease observed, nerve damage mutation Gene is Huntingtin discovered in 1993 + wild type allele (as of yet function unknown) + wild type allele makes normal functional protein –found most common in nature No signs of disease, no nerve damage Let HD be the mutant allele -Phenotypically will cause disease state HD+ HD Heterozygous for trait HD makes altered protein, “masks” wild F1 have HD symptoms (only one copy needed) ∴ allele is dominant to HD+ which is HD dominant recessive for protein function and HD phenotype Let HD+ be the wild type allele – phenotypically normal no disease state HD HD HD Homozygous for trait HD which is dominant Condition usually more severe in homozygous form • rare diseases, so to find individuals homozygous for dominant allele is very uncommon • ∴ an affected person in pedigree is most likely heterogyzote (Aa) • most pairings (in pedigree), likely to be heterozygous X a homozygous wild type i.e. dominant mutant allele is A wild-type allele is a+ Aa X a a • Two affected parents can have unaffected children unaffected i.e. Aa x Aa (1/4 will be normal) General Characteristics of Dominant Traits: General • Every affected person in the pedigree must have at least one affected parent (vertical) • The trait usually will not skip generations An affected heterozygous individual will, on average, transmit the mutant gene to half of his/her progeny i.e. dominant mutant allele is A wild-type allele is a (A a+) X (a+ a+) / A a+ / a+ a+ • Most dominant mutant genes that cause medical problems are in this category Huntington’s Disease: Huntington’s • late onset disease • usually don’t know have disease till after child bearing years • intellectual deterioration • severe depression • jerky, irregular movement • progressive death of nerve cells Dominant alleles that affect viability or fertility are usually lost from population or very low in frequency If Huntington’s disease is so severe, why does it persist in the population? Don’t forget rare recessives much more common (many single gene traits are recessive) in the population than dominants. Why? Pedigree of a dominant trait Pedigree Huntington’s disease • • • vertical path of disease strongly hints at rare dominant trait rare equally heritable from both mother and father not sex-linked equally when enough progeny present, we see that half of the offspring are when affected affected Pedigree of a dominant trait Pedigree Appears frequently in each generation Dominant traits like test cross test • view every mating between affected and unaffected as a test cross • if some progeny are unaffected then parent showing trait is heterozygous Wooly hair Autosomal vs. sex-linked traits Autosomal Autosomal trait – one that is conferred by a gene residing on a chromosome not involved in sex determination. The human genome consists of 46 chromosomes, 22 pairs of autosomes and 1 pair of sex chromosomes (the X and Y chromosome). Sex-linked trait – one that is conferred by a gene residing on the X or Y chromosome 22 pairs of Autosomal 1 pair pair sex sex Karyotype Recap: What is possible mode of inheritance for this pedigree? Can we say? Dominant? Father Aa+ heterozygous for dominant allele Mother is a+a+ (homozygous wild) Children would be ½ Aa+ and ½ a+a+ Recessive? Father is affected so homozygous recessive aa Mother is heterozygous Aa (carrier) Son is affected aa and daughter is carrier Aa As mentioned, would depend on the frequency of the allele in the general population.. That is how common is that allele If dominant only father would need to carry one copy of the allele to be affected In population with rare dominant (or recessive) chances are that would marry someone who is unaffected (normal wild) For it to be recessive, would need to have an affected marry a heterozygous If allele is very rare chances would be low that this would happen Need more generations to know for sure! ...
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This note was uploaded on 10/04/2011 for the course BIOL 139 taught by Professor Christinedupont during the Spring '10 term at Waterloo.

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