HUMAN GENETICS Disorders

Interpreting Pedigrees with Andrew Douch Interpreting Pedigrees the Fast Way –Example 1(6:42) Example 2 (6:46) 1. Is anyone with a phenotype different from parents? 2.Are there any girls with recessive phenotype who have a father or son with a dominant phenotype? Autosomal Dominant X-linked dominant Autosomal Recessive X-linked recessive

Autosomal Dominant: trait does not skip generations

Autosomal Recessive: tends to skip generations

X-linked dominant: both males and females affected does not skip generations Affected sons have an affected mother

X-linked recessive: more males than females affected Skips generations: affected sons from non-affected mothers

Testing for genetic disorders Ultrasound imaging-a sonogram made from passing high-frequency sound waves with a transducer through the abdomen (least invasive)

Testing for genetic disorders Amniocentesis-a small amount of amniotic fluid, which contains fetal tissues, is sampled Use cells for karyotyping

Testing for genetic disorders Chorionic villus sampling (CVS)-take a sample of the placental tissue for chromosomal abnormalities Can use cells for karyotyping

AUTOSOMAL RECESSIVE Autosomes = , chromosomes #1- #22

Cystic Fibrosis-ff On Chromosome 7 Autosomal recessive It causes the body to produce a thick, sticky mucus that clogs the lungs and digestive tract. On Chromosome 7 Autosomal recessive

One test is for salty skin CF salt test Salty skin (Mutations of the CFTR gene affect functioning of the chloride ion channels) thin (do not digest well) abnormal bowel movements CFTR video (8:18) describe 6 mutation disfunctions for 2 pts Ex Cr

Cystic Fibrosis (cont.) Most common fatal genetic disease in US today Most common in Caucasians Small Child CR Treatment (thumping) Thumping Vest (1:24) Living with CF (3:48) Daily meds

Cystic Fibrosis Chromosome 7 FF = no CF Ff = carrier ff = has CF (recessive) Life with CF (3:48)

Phenylketonuria (PKU)

PKU on chromosome 12 recessive Lacks enzyme to break down the amino acid phenylalanine (found in milk)

PKU (cont.) The breakdown products can be harmful to developing nervous systems Leads to mental retardation. Kate with PKU Movie

PKU Chromosome 12 Put on low protein diet Avoid phenylalanine

TAY SACHS Highest rate in Eastern European Jews, next Irish-Americans Results in degeneration of the nervous system. Chromosome 15 recessive Highest rate in Eastern European Jews, next Irish-Americans

Tay Sachs (cont) Lack enzyme to break down fat, accumulates in brain (poisons it) tt Chromosome 15 NOVA Online | Cracking the Code of Life | Watch the Program Here #3

Tay Sachs Disease is a fatal lipid storage disorder where a fatty substance (ganglioside) builds up in the nerve tissue and cells of the brain. This is caused by an insufficient enzyme called beta-hexosaminidase A that catalyzes the biodegration of gangliosides.

Tay-Sachs Symptoms Symptoms first appear at 4 to 6 months of age when an apparently healthy baby gradually stops smiling, crawling or turning over, loses its ability to grasp or reach out, and eventually becomes blind, paralyzed and unaware of its surroundings. Death usually occurs by age 4. Tay-Sachs PT (1:52)

Albinism Inability to manufacture pigments (melanin) in skin and eyes Autosomal recessive trait Chromosome 11

Albinism

Famous Albinos Andy Warhol, a famous artist “The Twins” in Matrix Reloaded Rock musician Edgar Winter, an albino.

Is this an advantage or disadvantage?

Different kinds of albinism affect chromosomes 1, 9, 10, 11, 15 and X (ocular albinism) Often rapid back and forth eye movement – lack of pigment in eyes.

Polar bears actually have black skin under all that white fur.

AUTOSOMAL DOMINANT on chromosomes 1-22

Sickle Cell Anemia Autosomal dominant disease Chromosome #11 Red blood cells collapse and clot blood vessels Found in African-Americans

Sickle-Cells Normal Red Blood Cells-like a donut Sickle-cells collapse, hard, clog vessels

Sickle-Cell Anemia Codominant SS = disease AS = carrier (somewhat resistant to malaria) AA =normal hemoglobin Living with SSA Plasmodium in blood - malaria

Sickle-Cell Complications 1.pain episodes 2.strokes 3.increased infections 4.leg ulcers 5.bone damage 6.yellow eyes or jaundice 7.early gallstones 8.lung blockage 9.kidney damage and loss of body water in urine 10.painful erections in men (priapism) 11.blood blockage in the spleen or liver (sequestration) 12.eye damage 13.low red blood cell counts (anemia) 14.delayed growth

Huntington’s Disease Woody Guthrie’s disease (folksinger 1960’s) Autosomal dominant Does not manifest itself until age 20’s - 30’s H=dominant disease

What is the chance of a child of a Huntington Mother having Hungtingtons?

Huntington’s 40+ CAG’s (build up protein clumps) Chromosome 4 Atrophy of brain Uncontrollable muscle spasms 40+ CAG’s (build up protein clumps) Huntington's Chorea Dance (5:33) Controls thinking, emotion, movement

Huntington’s Clumsiness Jaw clenching Loss of coordination and balance Slurred speech Swallowing and/or eating difficulty Uncontrolled continual muscular contractions Walking difficulty, stumbling Hostility/irritability Inability to take pleasure in life Lack of energy person with Huntington's also may exhibit psychotic behavior: Delusion Halluciations Inappropriate behavior (e.g., unprovoked aggression) Paranoia

Achondroplasia -Autosomal Dominant -chromosome 4 Achondroplasia: Genetic Causes (2:40)

Achondroplasia Dwarfism Average adult male height of 52 inches; average adult female height of 49 inches Dwarfism Achondroplasia: Genetics (2:20) short stature shortening of limbs, trident hands prominent forehead

FAQ Can short-statured couples become the parents of average-size children? AA=dead Aa=Achondroplasia aa=normal A a A a

FAQ Can short-statured couples become the parents of average-size children? AA=dead Aa=Achondroplasia aa=normal A a AA Aa aa A a X

Alzheimer syndrome Widespread nerve cell dysfunction and cell death in the brain Dementia (memory loss) Alzheimer's Disease: Medical Update (1:39) Life with Alzheimers (3:56)

Alzheimer Syndrome Autosomal Dominant Found on Chromosome 1, or 10, or 14, or 19, or 21 APO4, is a cholesterol-carrying protein linked to development a protein that forms plaque in the brain Alzheimer's neurology (1:01) Alzheimers' Disease: Neurology

Brain Loss

Early or mild stage: memory loss, especially of recent events difficulty in recalling names and conversations misplacing objects  becoming lost in familiar neighborhoods repeating stories and conversations difficulty in learning new information personality changes decreased motivation and drive easily upset or anxious 

Marfan Syndrome autosomal dominant disorder chromosome 15

Marfan’s: taller, pigeon chest Marfan's Video (2:45) Spidery fingers, enlargement of aorta

Michael Phelps Does Not Have Marfans X Extra Tall Athletes in their recruiting physical are tested for Marfans. Clarence Holloway of Louisville does have Marfan's syndrome (had open-heart surgery) Manute Bol did Died at age 47 Gheorge Muresan 7’7”

Marfan Syndrome a connective tissue disorder Affects skeleton, lungs, eyes, heart and blood vessels. unusually long limbs High arch palate Debated if Abraham Lincoln has Marfan’s.

SEX-LINKED DISORDERS On X chromosome

Hemophilia- “bleeder’s disease” New Hemophilia Treatment (48 secs) Living with Hemophilia (4:53)

Hemophilia blood tainted with AIDS 60 Minutes:Hemophiliacs Sue the Blood Donors Organizations

Hemophilia passed by queen victoria Blood does not clot normally Sex-linked recessive Missing AHF (clotting factor in blood) Czar Nicholas royal family

Royal Pedigree-Hemophilia

“bleeder’s disease” XHXh = female carrier XHY = normal male XhXh = female hemo XHY = normal male XhY = hemo male

Color Blindness More common in males Sex-linked (red and Green) on inability to perceive differences between some of the colors that others can distinguish. More common in males Sex-linked (red and Green) on X chromosome What it's like being color-blind? (3:35)

Color Blindness 3 seconds to determine number Ishihara Test for Color Blindness

Ishihara Test for Color Blindness The individual with normal color vision will see a 5 revealed in the dot pattern. An individual with Red/Green (the most common) color blindness will see a 2 revealed in the dots. Are You color blind? (2:26) Ishihara Test for Color Blindness

Color blindness=can’t tell certain colors Recessive on X chromosome = c XCXc = normal female (carrier) XcY = color-blind male

What numbers do you see?

Note: X and Y used

Need X and Y on Punnetts

Duchenne Muscular Dystrophy

MD Duchenne Muscular Dystrophy On Xm chromosome Weakens and degenerates muscles Found mostly in males mutation in the dystrophin gene

DMD absence of dystrophin, a protein that helps keep muscle cells intact. -Leg muscles first. -Calves often enlarged. -Eventually this weakness spreads to the arms, neck, and other areas.

DMD Onset ·Early childhood - about 2 to 6 years. Symptoms · Generalized weakness of muscle Wasting affecting limb and trunk Duchenne Timeline (5:43)

DMD Survival rare beyond late twenties. X-linked recessive (females are carriers).

Determination of disorder occurs on more than one chromosome POLYGENIC DISORDERS Determination of disorder occurs on more than one chromosome

SPINA BIFIDA is a fault in the spinal column in which one or more vertebrae (the bones which form the backbone) fail to form properly, leaving a gap or split. A Snapshot of Spina Bifida (4:52) 

Spina Bifida #6, #14 and others Gap in spinal column

Shunts often put in the brain to drain the fluid

Agent Orange Children with Spina Bifida whose parent was in contact with Agent Orange during the Vietnam War are compensated

Cleft Lip/Cleft Palate #11, #17, #22 A cleft is an opening in the lip, the roof of the mouth (hard palate) or the soft tissue in the back of the mouth (soft palate).

Clefts Bilateral Complete Cleft Lip/Palate Clefts occur more often among Asians and certain groups of American Indians than among whites. They occur less frequently among blacks.

Cleft lip/palate As you can imagine there are feeding problems #11, #22, #17 – Polygenic Unilateral Cleft Lip Repair (9:15)

Hypercholesterolemia polygenic dominant is the presence of high levels of cholesterol in the blood. lead to atherosclerosis (hardening of the arteries) additive effects of multiple genes (polygenic) yellowish patches consisting of cholesterol deposits above the eyelids.

Hypercholesterolemia

On Y chromosome SRY gene: male determining only on Y Testes determining factor

If you are born with no “X” chromosome- it is fatal NOTE: If you are born with no “X” chromosome- it is fatal If missing an autosome-it is fatal

X chromosome Sex-linked traits

Triple-X Syndrome triplo-X trisomy X XXX syndrome 47,XXX aneuploidy There is usually no distinguishable difference to the naked eye between women with triple X and the rest of the female population.

Triple-X Syndrome Although females with this condition may be taller than average, this chromosomal change typically causes no unusual physical features. Most females with triple X syndrome have normal sexual development and are able to conceive children.

Nondisjunction Chromosomes to segregate unevenly during meiosis Mistakes in Meiosis

Down’s Syndrome Trisomy 21 Extra fold over eye Sluggish muscles Mental problems

Trisomy 21 Karyotype

Nondisjunction

Turner’s Syndrome Adults with Turner syndrome are short, averaging around four feet, eight inches in height. Flap in neck Small breasts

But girls with Turner syndrome don't start life as very short individuals - they become short over time-do not develop sexually

Turner’s Syndrome 45 X0

Kleinfelter’s 47 XXY

Kleinfelter’s -Testes are small -breast growth (gynaecomastia) -poorly developed secondary sexual characteristics.

Men are sterile (no sperm). Klinefelter’s Men are sterile (no sperm).

Special Topics In Human Genetics

BARR BODIES So there is not excess of X info in females When a female is born one of her X chromosomes is inactivated = a Barr Body (early in embryonic development) Used to test femaledness at Olympics So there is not excess of X info in females

Calico Cat – X linked Only females have 3 colors (orange, black, white) Looks like “Pepper”

Multiple colors in cats mostly in females

GENETIC DISORDERS REFERENCE SHEET: Down Syndrome (Trisomy 21) Edward's Syndrome (Trisomy 18) Patau Syndrome (Trisomy 13) Klinefelter Syndrome (47, XXY) Turner Syndrome (45 XO) Metafemale (46XXX)-taller Autosomes (#1-22) so 44 if normal

Angelman Syndrome Deletion of Chromosome 15 If inherited from FATHER Symptoms: Short and obese, delayed development, frequent laughing

Angelman Syndrome

Prader-Willi Syndrome Deletion is inherited from mother’s chromosome 15 Hyperactive, chronic hunger, low muscle tone, obesity

Prader-Willi Syndrome Before and after controlled eating