Genetics in medicineLecture 3:Ch 10: 207-22human genome project: complete list of all human genes, khowledge of their location and structure, and catalogue of many variants in DNA sequence in individuals of different populations. Disease gene identification linkage analysis (family based) use pedigrees association analysis (population based) sample of individuals in a poulationMeiosis 1: homologous chromosomes pair and the pairs line up along meiotic spindle. paternal and maternal homologues exchane homologous segments by crossing over and creating new chromosomes that are a patchwork of alternation portions of grand parents chromosomes.

genetic marker: defined by any charactheristic located at the same position on a pair of homologous chromosomes that allows us to distinguish one homologous chromosome from anotherindependent assortment. if loci 1 and 2, with d/D and m.M are on different chromosomes, there will be four possible combinations of alleles. Dm, dM, DM, dm. half gametes are parental and half are non parental (if genes are unlinked). recombination frequency for these is .5. (zero if completely linked and don't recombine)syntenic: genes on same chromosomerecombination: when genes don't independently assort. RF is between 0-50 MU. smaller RF means closer the genes. phase: coupling is when alleles of a gene are on the same chrom, and repulsion if when they are on homologous chrom. measurement of theta (RF) is done with LOD score method (logarithm of the odds)more recombination in females than malesChapter 5: pp 59-83chromosome disorders, cytogenic disorders. if mom is older than 35, risk goes from 1% to 2%karyotype: chromosomes are frozen in metaphaseclinical indications for chromosome analysis: problems with early growth and devlopment, stillbirth and neonatal death, fertility problems, family history, neoplasia, pregnancy in older women. -peripheral blood is short lived, so fibroplasts, lynphoblastoid, and bone marrow cells are best-staining by-giemsa (g) banding, Q banding, Cbanding, R bandingchromosomes: metacentric: equal length arms submetacentric:off center centromere acrocentric: centromere near one end. 13, 14, 15, 21, 22. small masses of chromatin called sattelites that have genes encoding rRNA and repetitive sequences. telocentric: centromere at one end, with a single arm (not seen in human)Flourescence in situ hybridization: to examine the presence of absence of a particular DNA sequence or to evaluate the number or organization of a chromosome or chromosomal region. molecular cytogenetics DNA probes specific for individual chromosomes, chromosomal regions, or genes, can be used to identify particular chromosoma rearragmenets or to diagnose existence of an abnormal chromosome #. or gene or locus specific probes to detect location of a particular gene. repetitive DNA probes allow detection of sattelite DNA or other repeated elements at specific sites locus specific, sattelite DNA (ex centromere), and/or full chromosome probes probes that bind the entire length of a chromosome. FISH uses different flouorochromes to detect multiple probes simulatensouly(4 color) SKY(spectral karyotyping can do up to 24comparative genome hybridization (CGH) genomic level microarrays measure copy nu,ber of genomic DNA sequences, but not if they have been rearranged from normal position of genome. can show increased ratio for trisomy, and decreased ratio for monosomy females have more x than Y, makes have more Y than Xchromosome abnormalities aneuploidy abnormal chromosome # due to extra or missing chromosome which is associated with physical or mental maldevelopment or both heteroploid: a chromosome complement with any chromosome number other than 46 euploid:exact multiple of haploid chromosome # triploid 3n and tetraploid (Don't confuse with trisomy or monosomy) reciprocal translocations exchange of material between NON homologous chromosomes, not much phenotypic effect. monosomies are worse than trisomies. only monosomy X is viable. complete trisomies are viable for 13, 18, 21, x, y pericentric (include centromere) and paracentric (don't include centromere) inversions 46; XX and 46; XY are normalmost common cause of aneuploidy is nondisjunction (can also see premature separation of sister chromatixs in meiosis 1 instead of meosis 2, leading to chromatids segregating to oocyte or polar body, leading to unbalanced gamete

if in M1, gamete with 24 chromosomes (vs 23) contains paternal and maternal members of the pair. but if in M2, gamete with 24 contains both copies of either maternal or paternal centromere.if ndj occurs in mitosis in zygote, get mosaicismAbnormalities of chrom structure:chromosome breakage followed by reconstitution in an abnormal combination less common than aneuploidy balanced =chrom has normal complement of chromosomal material unbalanced-additional or missing material: abnormal pheno unequal crossing over, deletions, insertions, ring fragments, duplication of a part of a chrom leads to partial trisomy, deletion leads to partial monosomy for the genetic onfo on the corresponding segment of the normal homologue monosomy: haploinsufficiancy, wehere a single gene copy is insufficient for normal function fish (specific probes) ,banding (HIGH RES), and microarray can detect deletions deletions can be interstitial or ternimal robertsonian translocation: join 2 arocentric armsduplications: like deletions, can originate by unequal crossing over, or by abnormal segregation from meiosis.less harmful than deletion

inversion: when a single chromosme gets two breaks and is reconstituted with the break inverted. paracentric (not including centromere) and pericentric (including centromere). it's a balanced rearramgement so it usually doesn't lead to abnormal phenotype. BUT it can lead to abnormal gamete production because of inversion loops-if inversion os paracentric, can get acentric or dicentric chromosomes which wil be lethal-if pericentric, can lead to gametes with duplication and deficiency of chromosome segments.leads to abnormal karyotype/phenotypesome inversions are benign/small

translocation: exchange of info between nonhomologous chromosomesreciprocal: associated with mental problems and abnormal gametes/progeny. balanced. robertsonian: two acrocentric croms that fuse near centromeres and lose short arms. leads to 45 chromosomesInsertion:nonreciprocal: piece of one chrom inserts into another

Chapter 6:Down syndrome: Trisomy 21. most common if mom is over 35. maternal meiosis 1phenotype: hypotonia, low set ears, and flat nasal bridge, eyes have brushfield spots, simian crease on palm, mental retardation, many have congenital heart disease, risk of leukemia, early alzheimers95% due to trisomy 21 due to nondisjunction of ch 21 pair. otherwise robertsonian translocation (21q and 14or22 q). this has no relation to maternal age but correlated to mom being a carrier (sometimes but rarely dad). a few have 21q21q translocationcan detect down with cgh of CV or amnio cells

autosomal deletion syndromes: cri du chat syndrome terminal or interstitial deletion of short arm of chromosome 5 fish and cgh haploinsufficiencysex chromosome abnormality: delay of puberty, primary or secondary amenorrhea, infertitlity, ambiguous genitalia.x/y chrome aneuploudyless severe than autosomal disorrs because of X chromosome inactivation and low gene content of XXY, XXX, XYY, Xmosaicism more common than for autosomesTurner syndrome: short, webbed neck, low posterior hairline, wide slaced nipples, renal and cardio anomalies. edema in newborns. varying intelligence, worse cognition in those with a maternally derived X*. not usual mental retardation. (what is ring X?)45X(X0) or other karyotypes, like mosaic ones. cromosome constitution dictates phenotype. many are spontaneous abortions.Lecture 4: chapter 225,000 genes in a humanall cells are somatic but germ line cellsmitotic cell cycle

Lecture 5: chapter 7single-gene traits caused by mutations are considered mendelian-many during pediatric agehaplotype: a given set of alleles at al ocus or cluster of loci on a chromosome. pure dominant vs co-dominant (expression of both alleles, ex. ABO) vs. incompletely dominant/semi-dominant (when disorder is more severe in homo than heterozygote, ex: achondroplasia, familial hypercholesterolemia)penetrance: probability that the gene will have any phenotypic expression at all. if less than 100%, we call it reduced penetrance. failure of penetrance leads to skipping of generations.variable expressivity: when people with same genotype show varying severity of symptoms. congenital: disorder present at birth.Genetic heterogeneity: different mutations leading to same defect/phenotype. can be due to allelic heterogeneity (mutations at same locus, like in the case of cystic fibrosisthis is why CF patients can display different symptoms) or mutations at different loci *locus heterogeneity)when different mutant alleles in the same gene lead to distinct phenotypes, its called clinical or phenotypic heterogeneity. certain autosomal disorders (can be passed from father to son!) can affect one gender more than another. ex: male-limited precocious puberty. X-inactivation: normalizes the expression of most X linked genes in the two sexes. this is why females show mosaic expression, such as duchenne muscular dystrophy. this is what can lead to different phenotypes of females with the same x linked disease, since one female can shut off a different proportion of her X chromosomes than another.Fragile X syndrome: a common heritable form of mental retardation second to downsyndrome. there is a fragile site on the X chrom where the chromatin fails to condense properly during mitosis. due to a CGG repeat leading to methypation of cytosines in the promoter of FMR1. this interferes with replication and/or chromatin condensation. Carriers of permutations can develop adult onset problems fragile X associated tremor/ataxia syndrome. Females in this situation develop premature ovarian failure.Other diseases due to repeats: HD and myotonic dystrophyLecture 5- Chapter 9mutations: genome mutations: mutations that affect the # of chromosomes in the cell. nondisjunction/missegregationchromosome mutations: affect structure of chromosomesgene mutations: base pair substitutions, deletions, insertions, (DNA replication errors)missense: amino acid substitutionchange from pyrimidine to pyrimidine= transition .vice versa is a transversion.a common DNA modification involves methylation of cytosine residues, esp when they are to the 5 of a guanine. spontaneous deamination leads to transitions.dynamic mutation: trinucleotide repeats can expand durng gametogenesismicrosattelite: a kind of polymorphism- stretches of repeating nucleotide units.--> short tandem repeatsmajor histocompatibility complex: a large cluster of genes located on short arm of chromosome 6 classified into 3 categories, 2 of which are class 1 and 2 HLA genes. C1 and 2 genes encode cell surface proteins that play a critical role in the intiation of an immune response, in presentation of antigen to lymphocytes. foreign material must be displayed in the context of a c1 or c2 HLA molecule. class 1 MHC: HLA-A,B, C presents peptide to cd8 cells class 2 MHC: HLA- DP, DQ, DR presented to cd4 t cell rceptors- set of HLA alleles at the different C1 and C2 loci on a given chromosome together form a haplotype. alleles are codominant; each parent has two haplotype and expresses both.

Lecture 6: Chapter 4molecular cloning: isoate a particular gene or other DNA sequence in large quantities for further study. transfer DNA into a microorganism which is grown in culture and replicats your DNA with its own.Lecture 6: Chapter 15prenatal testing chorionic villus sampling amniocentesis Lecture 7: Chapter 8certain diseases are in part genetic, but have environmental influence.modifier genes affect severity or occurrence of a mendelian disordermany diseases with complex inheritance is that affected individuals cluster in families: familial aggregationlambda= prevalence of disease in relatives/ prev in general popdisease concordance less than 100% in mz twins is evidene that non genetic factors play a role in the disease, maybe x inactivation, enviro, somatic mutation, somatic rearramgenents in immune cells. but MZ twins show a lot of concordance of disease/behaviors, even if enviro is differentenvironmental and modifier genes can affect illnesses such as CFsome patients with digenic retinitis pigmentosa show mutations on different unlinked genesapoe gene has three alleles, e2,3,4. it si a protein component of the LDL particle and a constituent of the AMYLOID PLAQUESin AD and binds the amyloud beta peptide. a genotype with the e4 allele was found 2 to three times more frequently among patients. risk of AD is higher with 2 e4 alleles, as they have earlier onset. less earlier for e3/4 .e4 predisposes boxers to AD