Human Genetics - Lecture notes 1 PDF

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Dr. Beal...

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I.

Human Genetics → APPLY, INTERPRET pedigree

II.

Traits w/ Mendelian Inheritance → CC Recessive, dominant disorders

III.

Traits w/ Non- Mendelian Inheritance → CC Types of disorders

IV.

Genetic Testing → CC types of tests

I.

Human Genetics A. Introduction 1. Study of inherited variance in humans 2. Difficulties in studying human genetics a) Few offspring b) Long generations c) Cant experiment on humans 3. How to study human genetics a) Population studies of large extended families b) Analyze mating that have already occurred rather than manipulating c) Medical attention to human genetic diseases d) “Natural experiment” → how Garrod figured out Mendel’s rules applied to humans 4. Can also use DNA sequencing a) DNA sequencing → many questions, extended relatives → genetic basis of similarities and differences 5. Historical Example: Habsburgs a) European royal family b) Prominent from 1100s to 1780 (or 1918) c) Detailed records of mating and phenotypes (e.d hemophilia)

B. Pedigree Analysis 1. Pedigree → Family tree that shows inheritance patterns over several generations a) Can determine inheritance pattern ( dom or rec) b) Based on distribution of that trait c) Often used by genetic counselors II.

Traits w/ Mendelian Inheritance

In general … Genes → proteins → function Defective allele → defective protein or none at all → no function A. Recessively Inherited Disorders 1. Auto somal recessive → non sexlinked 2. Dominant allele makes enough protein 3. Heterozygote = carriers

4. Everyone carries something a) Most human genetic disorders are single-locus autosomal recessive traits 5. To have a disorder… a) Must be homozygous recessive b) 2 copies of defective allele required

c) Parents of most affected individuals are carriers d) Example: Sickle Cell Disease (1) Most common inherited disorder among ppl of African Descent (2) Due to Single AA substitution in hemoglobin e) 2 Outcomes (1) Cells destroyed immediately (a) Lower O2 carrying capacity → anemia (2) Cell clumps together (a) Slow blood flow, block capillaries → tissue damage pain f) Sickle Cell Heterozygous (1) Normal and abnormal hemoglobin both made (2) Often no phenotypic difference g) Sickle Cell and Malaria Resistance (1) Malaria: Intracellular parasite of RBCs (2) Heterozygotes resistant (3) Evolutionary implications: (a) Sickle- cell allele favored in regions with endemic malaria (4) Heterozygote Advantage B. Dominant Inherited Disorders 1. Autosomal dominant 2. Much rarer genetic disorders 3. Only one defective allele required 4. Example: Achondroplasia a) Form of dwarfism

b) Dom allele→ heterozygous have dwarf phenotype III.

Traits w/ Non- Mendelian Inheritance A. Changes to Chromosome number 1. Differences in # of chromosomes can cause disease 2. Normal state → Disomy a) 2 copies of chromosome, 1 homologous pair) 3. Changed by Nondisjunction***

a) Results in Aneuploidy 4. Aneuploidy a) Presence of abnormal # of particular chromosome b) Extra or missing copy c) Trisomy: having 3 of a chromosome → 2n + 1 d) Monosomy: Lacking 1 member of a pair of chromosomes → 2n -1 5. Aneuploidy Viability a) In humans, monosomies for all autosomes inviable b) Most trisomies also inviable c) Estimates that >50 % of pregnancies end before 8 weeks 6. Trisomy 21 a) Down Syndrome, named for Langdon Down b) Extra 21st Chromosome, complete or partial c) Generally due to nondisjunction in the egg d) Frequency increases with maternal age e) Symptoms (1) Abnormalities of face, hands, tongue, eyelids (2) Slow physical and mental development

(3) Short stature (4) Prone to heart malformations, respiratory disease, and leukemia 7. Aneuploidy of Sex Chromosomes a) Differences in number of sex chromosomes relatively common b) Many sex chromosome aneuploidies are viable but infertile c) Common: (1) XO (2) XXY (3) XYY 8. Turner Syndrome - XO a) 44 autosomes and 1 X chromosome b) Denotes as “XO” and “45”, “XO” -0 indicates absence of 2nd sex chromosome 9. Klinefelter Syndrome - XXY a) 44 autosomes, 2 X chromosomes, 1 Y b) Denotes XXY or 47, XXY 10. XYY a) 44 autosomes, 1 X chromosomes, 2 Y b) Phenotypically normal c) Usually fertile → do not transmit extra Y d) Discredited theory - “supermales” B. Changes to Chromosome Structure 1. Due to errors in meiosis, radiation, or other mutagens 2. 4 types

3. Philadelphia Chromosomes

a) Results in a number of types of leukemia C. Genomic Imprinting

1. Epigenetics, This idea that you can change expression pattern without changing the DNA sequence → through DNA Methylation a) Expression patterns are heritable b) Allele from mom + Allele from dad (both at different levels) → due to methylation pattern 2. Example: Mouse Insulin- like Growth Factor

a) Happens in humans → behavioral phenotype (1) Prader-Willi (a) Children will eat themselves to death because it is mom's genes being expressed (2) Angelman syndrome

(a) Child demands attention and is chery all the time IV.

Genetic Testing

Earlier diagnosis → better chance of prevention or alleviation A. Fetal testing: Genetic tests done before birth 1. Amniocentesis 2. Chorionic Villus Sampling (CVS) 3. Non-invasive prenatal screening/testing 4. Amniocentesis v.s CVC

B. Newborn screening

1. Some genetic disorders detected at birth a) Example: Metabolic Disorders 2. Example: Phenylketonuria a) Every newborn in US Tested for PKU b) Normally: Phenylalanine → tyrosine c) PKU: Phenylalanine → phenylketones (toxic) d) Phenylketones accumulate → damage to nervous system → mental impairment...