Genetics Congenital & Genetic Disorders

1. GeneticsCongenital & Genetic Disorders Pathophysiology

2. Review of Human Genetics • Genes, diploid, alleles, traits • Genes = segment of DNA responsible for a particular trait • Gene locus = where it’s located on the chromosome • Human genome project • Diploid = when one’s chromosomes are in matched pairs • One chromosome in the matched pair ---- from the father • One chromosome in the matched pair from the mother • These sister chromosomes called homologs • Alleles = genes that have the same locus (location) on sister chromosomes • Allele = each form of the same gene • Trait = what both alleles eventually code for • 2 genes(alleles) are responsible for most traits • One from the mother; one from the father • Mitosis & meiosis • Mitosis = process of cell replication where DNA is replicated (“mutations”) • For maintenance and growth of the organism • Chromosomes number stays constant • Meiosis = process of making sex cells (gametes) • For sexual reproduction • Chromosome number is reduced by half SEE NEXT SLIDE

3. MEIOSIS= nuclear division mechanism with which the parental chromosome number is reduced by half • Thus, going from a diploid cell to a haploid cell • purpose = to make gametes ( sex cells) • Meiosis has 2 divisions (note that mitosis has only one division) 1. MEIOSIS I • phases = Prophase I, Metaphase I, Anaphase I, Telophase I • called “reduction division” • In prophase 1, when homologs synapse --- called “tetrad” since chromosomes are already in chromatid form • Key = Homologs separate 2. MEIOSIS II • phases = Prophase I, Metaphase II, Anaphase II, Telophase II • called “mitotic division” • Key = Chromatids separate

4. Special Events in Meiosis I • CROSSING OVER • In Prophase I the homologs align up (i.e. synapsis) • Remember that each chromosome is in the chromatid form • non-sister chromatids exchange whole segments or individual genes where they touch (where they touch is called a chiasma) • When the homologs align, there are 4 chromatids that are close together • Key = during Prophase I , alleles are exchanged between homologs via “Crossing Over” • RANDOM ASSORTMENT • In Metaphase I the homologs align at the spindle equator • they align at random • Thus, the male homologs & female homologs are interchanged at random • Remember what genetic products are interchanged: • Crossing Over during Prophase I - - - - - - mixes GENES • Random Assortment during Metaphase I - - mixes CHROMOSOMES

5. Reasons for Genetic Diversity • [1] random fertilization • Mature woman ovaries = 1 million ova • Mature man sperm = 10 million/ ejaculate • Possibilities = 10 million x 1 million = 10 trillion • [2] crossing over • Occurs in prophase I • Mixes genes • [3] independent assortment • Occurs in metaphase I • Possibilities = for diploid organisms put 2 to the power determined by the haploid number of chromosomes • 223 = 8. 3 million

6. Vocabulary • Dominant allele = in large case; fully expressed • A dominant allele masks the expression of a recessive allele • Recessive allele = in small case; not expressed unless both alleles are recessive • True breeding(same as homozygous) • All offspring same as parent • The inheritance of identical alleles for a particular trait • Hybrid breeding(same as heterozygous) • The inheritance of non-identical alleles for a particular trait • Trait expression • Homozygous dominant = pair of identical dominant alleles • Homozygous recessive = pair of identical recessive alleles • Heterozygous = pair of non-identical alleles • Genotype = actual genes one has for a trait • Phenotype = the appearance one sees for that particular trait • If appearance is the dominant expression you are either homozygous dominant or heterozygous • If appearance is the recessive expression you can be only homozygous recessive

7. Inheritance pattern in humans (3 types) [Of 23 pairs of chromosomes: 22 = autosomes, 1 = sex chromosomes] • (1) Autosomal recessive • Commonest type of human inheritance • Ones gets both recessive genes for a trait • The heterozygote is a carrier; thus can skip generations • Incomplete dominance =when carrier has “a little disease” (Ss) • Includes: • Albinism • Sickle-cell anemia • Cystic fibrosis • Tay-Sachs disease • Pnenylketonuria

9. (2) Autosomal dominant • If have one or both dominant genes, the trait is expressed • There are no carriers • Can get codominance --- human ABO blood type • Includes: • Huntington’s chorea • Polycystic kidneys • Marfan’s syndrome • Polydactyly

11. (3) X-linked recessive • Clues that hint you are dealing with X-linked recessive trait • Males show phenotype much more than females • A son cannot inherit the recessive allele from his father • A daughter can inherit the recessive allele from her father • If mother a carrier– there is a 50% chance that each son will inherit the allele • Includes: • Color blindness • Hemophilia • Muscular dystrophy

12. Family pedigree for an X-linked recessive trait

14. Congenital Diseases • Def: = those diseases present at birth • Note that not all genetic diseases present at birth • Congenital diseases include: • (1) Developmental diseases • Those that arise spontaneously during gestation • Exp = failure of testis to descend • Those that are secondary to environmental problems • From trauma • From poisons (teratogenic agents) • From poor nutrition of mother during gestation • (2) Genetic diseases • Single gene disorders --- nucleotide mutation • Chromosomal defects • Usually occurs during mitosis • Multifactoral disorders • Polygenic (exp = diabetes) • Genetic tendency + environment (exp = lung cancer)

15. Genetic Diseases • Single gene disorders • Classified by inheritance pattern • Chromosomal diseases • 2 types • Structural change of the chromosome • Deletion = cause most serious problems and/or death • Translocation = broken part of chromosome becomes attached to non-homologous chromosome * Reciprocal or non-reciprocal (see next slide) • Change in chromosome number • Caused during meiosis by nondisjunction • Euploidy = normal number of chromosomes • Aneuploidy = abnormal number of chromosomes * Exp = turner’s syndrome = monosomy X Down’s synd. = Trisomy 21

17. Multifactoral diseases • May be a combination of environmental factors & genetic tendency • Exp = lung cancer, “not so smart” people, colon cancer • These may be polygenic • Exp = deafness, diabetes • Genetic testing • Karyotype • Gross structure chromosomal map • Genome • Loci specific chromosomal map • Analyzing the genes nucleotides • Blood tests looking for biochemical defect • Amniotic fluid analysis --- looking for biochemical defect

18. Down’s Syndrome • Called trisomy 21 • Seen more frequently as pregnant woman get older • Key = age 35 when risk increases dramatically • Physical signs • Small, flat head with low-set ears • Slanted eyes sometimes with epicanthal fold • Mouth hangs open with large protruding tongue • Simian crease • Short stature • Space between 1st & 2nd toe • Short little finger • congenital form of mental retardation associated with other findings which include: • congenital heart defects (commonest = ASD) • etiology = genetic defect ( commonest = trisomy 21) • More common in older pregnant women • incidence at age 35 = 1/650 • incidence at age 40 = 1/60 • diagnosis = karyotype