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 dominantAutosomal Recessive X-linked recessive

Autosomal Dominant:trait does not skip generations

Autosomal Recessive: tends to skip generations

X-linked dominant: both males and females affecteddoes 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

It causes the body to produce a thick, sticky mucus that clogs the lungs and digestive tract.

On Chromosome 7Autosomal recessive

One test is for salty skinCF 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)

PKU

Phenylketonuria (PKU)

PKU on chromosome 12recessive

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

PKUChromosome 12Put on low protein

dietAvoid

phenylalanine

TAY SACHS

Results in degeneration of the nervous system.

Chromosome 15recessive

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 | Crac

king 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 SymptomsSymptoms 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 eventuallybecomes 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 traitChromosome 11

Albinism

Famous Albinos

Andy Warhol, a famous artist

Rock musician Edgar Winter, an albino.

“The Twins” in Matrix Reloaded

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 DOMINANTon chromosomes 1-22

Sickle Cell Anemia

Autosomal dominant disease

Chromosome #11Red 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

CodominantSS = diseaseAS = carrier (somewhat resistant to

malaria)AA =normal hemoglobinLiving with SSA

Plasmodium in blood - malaria

Sickle-Cell Complications1.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’sChromosome 4Atrophy of brainUncontrollable

muscle spasms40+ 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 4Achondroplasia: Genetic Causes (2:40)

Achondroplasia

DwarfismAchondroplasia: Gen

etics (2:20)

short statureDwarfismshortening of limbs, trident handsprominent forehead

Average adult male height of 52 inches; average adult female height of 49 inches

FAQ

Can short-statured couples become the parents of average-size children?

AA=deadAa=Achondroplasiaaa=normal

A a

A

a

FAQ

Can short-statured couples become the parents of average-size children?

AA=deadAa=Achondroplasiaaa=normal

AA Aa

Aa aa

A a

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 Syndromeautosomal

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

Clarence Holloway of Louisville does have Marfan's syndrome (had

open-heart surgery)

XGheorge Muresan7’7”

Extra Tall Athletes in their recruiting physical are tested for Marfans.

Manute Bol didDied at age 47

Marfan Syndrome a connective tissue

disorderAffects skeleton,

lungs, eyes, heart and blood vessels.

unusually long limbsHigh arch palateDebated 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

XhXh = female hemo

XHY = normal male

XhY = hemo male

Color Blindness

inability to perceive differences between some of the colors that others can distinguish.

More common in malesSex-linked (red and Green) on X chromosomeWhat 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)

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 DystrophyOn Xm chromosomeWeakens and degenerates

musclesFound mostly in malesmutation 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).

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 othersGap 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

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).

#11, #17, #22

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)

Hypercholesterolemiapolygenic 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 chromosomeSRY gene: male determining only on YTestes determining factor

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-Xtrisomy XXXX syndrome47,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 21Extra fold over eyeSluggish musclesMental 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.

Klinefelter’s

Men are sterile (no sperm).

Special Topics In Human Genetics

BARR BODIES

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 15If 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