GeneticsGeneticsCongenital & Genetic DisordersCongenital & Genetic Disorders

PathophysiologyPathophysiology

Review of Human GeneticsReview 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

• 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

Special Events in Meiosis ISpecial 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

Reasons for Genetic DiversityReasons 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

• 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

• 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

– (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

– (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

Family pedigree for an X-linked recessive trait

Congenital DiseasesCongenital 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)

Genetic DiseasesGenetic 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

• 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

• 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

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