Sex-Linked Traits Traits that are controlled by genes on the sex

chromosomes are called sex-linked traits.

Because males have only one X chromosome, they are affected by recessive disorders found on the X chromosome more than females.

Females are less likely to express a recessive sex-linked disorder on an X chromosome, because the other X chromosome may have a dominant allele, making them carriers.

X-Linked Disorders

• All sex linked disorders are x-linked

• Almost all X-linked are recessive.

• Several genes on “Y” all related to spermatogenesis

• Male mutations in “Y” are infertile, hence no Y-linked inheritance.

• Some X CH genes homologues mapped on Y CH but no mutational disorders described.

X-Linked Disorders

• X-Linked Recessive Inheritance:

• Small number of well-defined clinical conditions

• Most part of “Y” not homologous with “X”, so mutant genes unpaired

• So male is called Hemizygous for X-linked mutant genes

• Disorders mostly expressed in males

X-Linked Disorders

• X-Linked Recessive Inheritance:

• Characteristic Features:

• Affected male Sons unaffected, daughters are carriers

XY + XX XX XX XY XY

• Heterozygous woman Sons 1 chance in 2 of disease

XY + XX XX XX XY XY

X-Linked Disorders • X-Linked Recessive Inheritance:

• Heterozygous female no full phenotypic disease paired normal

allele

• THEORETICALY POSSIBLE????

XY + XX XX XX XY XY ?????

Above almost impossible bcz of the Random Inactivation of one X CH in females

Moreover the % itself is 1 in 2 daughter and 1 daughter in 4 children

Moreover it’s remotely possible that a diseased male always marries a carrier female and always a female is born???? Increasing the chances of homozygous female.

X-Linked Disorders

• X-Linked Recessive Inheritance:

• E.g., G6PD deficiency Favism drug induced hemolysis

• Males hemizygous so all RBC can be hemolyzed

• But in females, bcz of X-inactivation, some RBCs from BM may be with erroneous normal allele inactivation

• So hemolysis can be present in females carriers too, but less severe than males

X-Linked Disorders

• X-Linked Dominant Inheritance:

• Fewer

• Caused by dominant disease alleles on X Ch

• Affected heterozygote female half sons, half daughters

• xy + Xx xX xx Xy xy

• Affected father no son but all daughters affected if mother unaffected

• Xy + xx Xx Xx xy xy

• E.g., Vitamin D – resistant rickets

Sex-linked traits

Hemophilia is another sex-linked trait that causes delayed blood clotting.

Most sex-linked traits like color blindness and hemophilia affect males more than females.

Male pattern baldness is technically an autosomal trait, but it acts like a sex-linked trait.

Male Pattern Baldness

The gene for baldness is recessive in females, but dominant in males.

Males can either be heterozygous or homozygous dominant.

Females must be homozygous recessive to be bald.

Calico Cats

Males can either be black or orange.

Females can be black, orange, or calico.

This is caused by one of the X chromosomes becoming inactive in female cats.

X-Linked Dominant Inheritance

Polygenic Traits

Genes that are controlled by multiple genes at the same time are called polygenic traits

One characteristic of polygenic traits is that there tends to be a higher frequency of intermediate forms of a trait.

When graphed, the frequency of phenotypes for polygenic traits appears as a bell-shaped curve.

Some examples of polygenic traits are skin color, eye color, and height.

Polygenic Traits (Skin Color)

Polygenic Traits (Eye Color)

Polygenic Traits (Height)

COMMON GENETIC DISORDERS

• Gaucher Disorder

• Huntington’s Disorder

• Hemophilia

• Parkinson’s Disorder

• Sickle Cell Anemia

• Cystic Fibrosis

• Down Syndrome

• Alzheimer’s Disorder

• Thalassemia

• Tay-Sachs Disorder

GAUCHER DISORDER

• Gaucher disease is a genetic disorder handed down from

generation to generation

• It is the most common of a genetic disorder

• Caused by the deficiency of an enzyme β-

glucocerebrocidase

• The fat can not be broken down and is stored primarily in

the liver and spleen.

• Other body organ, tissues and bones are also effected , in

rare cases it may also accumulates in the brain.

GENERAL SIGNS AND SYMPTOMS

• Bone pain and fractures

• Easy bruising

• Fatigue

• Seizures

• Liver and spleen enlargement

HEMOPHILIA

• Hemophilia is the oldest known bleeding disorder.

• It is sex-linked disorder, of which it appears mostly in males.

• Hemophilia is like any other sex-linked disorder, the hemophilia gene is on the X chromosome.

• 2 types of hemophilia :

• Hemophilia A: Lack of the blood clotting protein factor VIII.

• Hemophilia B: Lack of the blood clotting protein factor IX.

• Symptoms :

• Main symptom is once bleeding starts the child bleeds longer than normal.

• It may include; Nosebleeds, bleeding for no reason, blood in the urine or stool and bleeding into a joint, which can cause tightness, swelling and pain.

Types of Genetic Disorders ●Hemophilia prevents blood clotting.

●It is a recessive sex-linked disorder, found on the X sex chromosome.

●It is dangerous because even small wounds can cause unnecessary bleeding and even death through blood loss.

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Pedigrees

●Below is a sample of a pedigree from a family which carries hemophilia.

Queen Victoria's Pedigree (Hemophilia)

..HEMOPHILIA TREATMENT Clotting factors: Given in differing doses

according to the weight of the individual and the severity of the bleeding.

Recombinant DNA Techniques: Clotting factor genes are grown synthetically.

Clotting factor products from human blood plasma are not used due to chances of being contaminated with viruses such as HIV or Hepatitis.

During the 1990s it became possible to prepare synthetic (recombinant) factors, using specially prepared mammalian cells and these recombinant concentrates are now widely used.

..HEMOPHILIA RESEARCH Gene Therapy

› A major focus of research in hemophilia centers.

› Because only one defective gene is involved, replacing that gene effectively may cure hemophilia.

› Although gene therapy may eventually replace treatment for individuals with hemophilia, it will not eliminate defective genes in carriers, who could still pass hemophilia to their children.

› Currently studies are being conducted for type B hemophilia to determine the safety of the gene transfers.

PARKINSON’S DISEASE

• Parkinson’s disease is a neurological condition that has a genetic component next to Alzheimer’s.

• The chances of getting developing Parkinson’s gets higher as age increases.

• Causes of Parkinson; DOPAMINE chemical produced in the middle part of the brain that is responsible for organizing coordinated movements and to send this signal to the control centers of the brain.

• In Parkinson's chemical production less and functioning starts to shut down slowly and patient begins to lose control over vital voluntary movement.

• Symptoms; Memory loss, blurriness and lack of postural stability.

SICKLE CELL ANEMIA

• Sickle cell anemia is blood related disorder that affects the hemoglobin molecule and causes the entire blood cell to change shape under stressed conditions.

• In sickle cell anemia hemoglobin molecule is defective.

• Round form of blood cells changes into long, rod-like structures which become stiff and assumes sickle shape so cell failed to carry oxygen.

• Normal red blood cells live 120 days in the bloodstream, but sickled red cells die after about 10 to 20 days.

Types of Genetic Disorders

●Sickle Cell Disease is where a person's blood cells are shaped differently. ●The 'sickle' shape of blood causes it to clot in vessels and

cause blockage and carries less oxygen.

●The allele for the disease is codominant with the normal allele.

● A person with one recessive and one dominant allele will produce half normal blood cells, half sickle.

●A person with two recessive alleles will produce only sickle cells.

Autosomal Recessive Dz’s • Sickle Cell Disease

– Genetics and Cell Level: – Point mutation in Beta-globin chain Glutamic acid to Valine

Africans are most commonly affected

Autosomal Recessive Dz’s

• Sickle Cell Disease –Clinical Presentation:

• Heterozygotes usually clinically silent but added protection to malaria

• requires > 90% HbS to sickle in systemic vasculature exception is in the renal papilla where oxygen tension is low enough to induce sickling but sometimes renal papillary necrosis

Autosomal Recessive Dz’s

• Sickle Cell Disease –Clinical Presentation:

• Homozygotes

• Presents with sickle cell vaso-occlusive crises

–Chest pain , bone pain

– Fever, stroke

–Abdominal pain

• gallstones

–Dactylitis

• painful swelling of the hands and feet

TREATMENTS OF SICKLE CELL ANEMIA

›Antibiotics

› Pain-relieving Medications

› Supplemental Oxygen

› Blood Transfusions

›Health maintenance starts with early diagnosis

THALASSEMIA

• It is a blood related genetic disorder which involves the absence or errors in genes responsible for production of hemoglobin.

• The severity of disease depend on the mutations involved in the genes and their interplay.

• Hemoglobin has 2 sub units referred as alpha and beta, chromosome 16 responsible for α sub unit and chromosome 11 for β sub unit, lack of particular sub units determine the type of thalassemia.

• Symptoms; Reduce fertility or even infertility, jaundice, paleness, poor appetite

Autosomal Recessive Dz’s

• PKU

– Genetics and Cell Level:

• Defect in phenylalanine hydroxylase which converts Phenylalanine to Tyrosine

Autosomal Recessive Dz’s

• PKU

– Clinical Presentation: The mother's body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth

– Mental retardation & seizures,

– Albinism

– “musty odor” to urine and sweat

– Misc:

• Very treatable diet low in Phe and high in Tyr

• Newborn screening is Mandatory!

PHENYLKETONURIA (PKU)

Rare metabolic autosomal recessive disorder

Affects protein breakdown in the liver resulting in mental retardation & genetic Mutation occurs on Chromosome 12

The mutated gene is supposed to code for a protein which produces phenylalanine hydroxylase

Without phenylalanine hydroxylase, phenylalanine (found in protein rich foods) cannot be converted to tyrosine

Excess phenylalanine in the body will result in mass production of phenylpyruvic acid

Phenylpyruvic acid cannot be absorbed by the kidney and thus excess phenylalanine and phenylpyruvic acid enters cerebrospinal

fluid and then the brain causing severe mental retardation.

PKU • Phenylalanine is an essential amino

acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu… etc.

• A low protein diet must be followed. • Brain damage can result if the diet is

not followed causing mental retardation…and mousy body odor (phenylacetic acid is in sweat).

...PHENYLKETONURIA(PKU)

Phenylketonuria or PKU People with PKU cannot consume any product

that contains aspartame.

PKU is a metabolic disorder that results when the PKU gene is inherited from both parents (recessive or dominant? Monogenic or chromosomal?)

….SYMPTOMS AND EFFECTS OF PKU

If Untreated in Infants:

•Severe brain damage

•Epilepsy

•Behavioral Problems

•Stunted growth

Symptoms Throughout Life if Treatment is not Followed Closely:

•Musty body odor

•Increased muscle tone

•Fair skin ,Vomiting, Active muscle tendon reflexes

TAY SACHS DISEASE

• Tay-sachs disease is a fatal genetic disorder in which harmful quantities of a fatty substance called Ganglioside GM2 accumulate in the nerve cells in the brain.

• This is caused by a decrease in the functioning of Hexosaminidase A enzyme.

• Genetic mutation of HEXA gene on chromosome 15

• Its abnormal activities causes an accumulation of fat in the nerve cells leading to paralysis, dementia, blindness and even death.

• This disease/disorder is autosomal recessive which means that an individual must inherit both the two defective genes, one from each parent.

ALZHEIMER’S

• Alzheimer's is a form of dementia that causes changes in the brain.

• Also affects a person’s memory, mood and behavior.

• Disease mostly affects people over 65.

• There is no specific test for Alzheimer disease however physician are able to look at a person medical history and give a physiological and memory tests to see how efficient the brain is.

• Symptoms;

Memory loss etc

Autosomal Trisomies

• Down Syndrome (Trisomy 21)

• 95% of cases due to meiotic nondisjunction of homologous chromosomes

• Associated with advanced maternal age

– 1:1500 at maternal age 20-24

– 1: 210 at maternal age 35-39

– 1: 25 at maternal age >45

– 4% of cases due to Robertsonian translocation • Long arm of chrom 21 is attached to another

chromosome and is kept diploid during gametogenesis

– 1% of cases due to Down mosaicism

Autosomal Trisomies • Down Syndrome (Trisomy 21)

– Most common chromosomal disorder and most common cause of congenital mental retardation

– Diagnosis done by triple screen • decr a-fetoprotein, decr estriol, incr. b-hCG • Quad screen is above plus inhibin A (incr is +) • U/S shows increased nuchal translucency

– Clinical Presentation: • Mental retardation, flat facies, prominent

epicanthal folds, simian crease, duodenal atresia, congenital heart dz (septum primum type ASD), hypotonia

– Misc: increased risk of ALL and Alzheimer's dz

Down Syndrome

Nondisjunction If chromosomes fail to separate properly during

meiosis, the gametes will not end up with the right number of chromosomes.

Later on during fertilization if the egg or sperm contains one of these abnormalities, a nondisjunction may occur.

If a zygote ends up with one extra chromosome, this results in a disorder called a trisomy (2n + 1)

If a zygote ends up with one less chromosome, this results in a disorder called a monosomy (2n - 1)

Nondisjunction

Disorders caused by Nondisjunction

Down syndrome – result of an extra chromosome number 21 (often called trisomy 21).

Symptoms include short stature, heart defects, and mental disability, increased risk of infection.

About 1 in 800 children born in the U.S. have Down syndrome.

Down Syndrome Karyotype

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Types of Genetic Disorders ●Down Syndrome is a form of mental retardation and physical abnormalities.

●It is caused by a duplicate 21st chromosome. Instead of two, they have three 21st chromosomes.

●This occurs when the chromosomes fail to seperate during meiosis.

…INDIVIDUALS WITH DOWN SYNDROME

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TREATMENT OF DOWN SYNDROME

• There is no single, standard treatment for Down syndrome. Treatments are based on each individual's physical and intellectual needs as well as his or her personal strengths and limitations.

• Treatment Therapies

Physical therapy includes activities and exercises that help build motor skills, increase muscle strength, and improve posture and balance.

Speech-language therapy can help children with Down syndrome improve their communication skills and use language more effectively.

Occupational therapy helps find ways to adjust everyday tasks and conditions to match a person's needs and abilities.

Emotional and behavioral therapies work to find useful responses to both desirable and undesirable behaviors.

Other Disorders caused by Nondisjunction

Turner's syndrome – (XO) Women with only one x chromosome. Symptoms include short height, webbed neck, lack of underarm and pubic hair, and underdeveloped ovaries.

Klinefelter's syndrome – (XXY) Symptoms in males include tall height, low IQ scores, speech and language difficulty, sterility.

Kleinfelter’s syndrome (or Klinefleter’s)

• Disorder occurring due to nondisjunction of the X chromosome.

• The Sperm containing both X and Y combines with an egg containing the X, results in a male child.

• The egg may contribute the extra X chromosome.

XXY

• Males with some development of breast tissue normally seen in females.

• Little body hair is present, and such person are typically tall, have small testes.

• Infertility results from absent sperm.

• Evidence of mental retardation may or may not be present.

Turner’s • Turner syndrome is associated with

underdeveloped ovaries, short stature, webbed, and is only in women.

• Bull neck, and broad chest. Individuals are sterile, and lack expected secondary sexual characteristics.

• Mental retardation typically not evident.

• Chromosomal or monogenic?

Turner’s Syndrome (XO)

SEVERE COMBINE IMMUNODEFICIENCY (ALYMPHOCYTOSIS/GLANZMANN–RINIKER SYNDROME /SEVERE MIXED

IMMUNODEFICIENCY SYNDROME/THYMIC ALYMPHOPLASIA) Severe combined immunodeficiency (SCID) represents a

group of rare, sometimes fatal, congenital disorders characterized by little or no immune response. The defining feature of SCID, commonly known as "bubble boy" disease, is a defect in the specialized white blood cells (B- and T-lymphocytes) that defend us from infection by viruses, bacteria and fungi. Without a functional immune system, SCID patients are susceptible to recurrent infections such as pneumonia, meningitis and chicken pox, and can die before the first year of life. Though invasive, new treatments such as bone marrow and stem-cell transplantation save as many as 80% of SCID patients.

• All forms of SCID are inherited, with as many as half of SCID cases linked to the X chromosome, passed on by the mother.

• It is also known as the bubble boy disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, become famous for living in a sterile environment.

TYPES OF SCID

• X-linked severe combined immunodeficiency

• Adenosine deaminase deficiency

• Purine nucleoside phosphorylase deficiency

• Reticular dysgenesis

• Omenn syndrome

• Bare lymphocyte syndrome

• JAK3{Janus Kinase-3}

TREATMENT OF SCID

• The most common treatment for

SCID is bone marrow transplantation.

• David Vetter, the original "bubble boy", had one of the first transplantations, but eventually died because of an unscreened virus, Epstein-Barr (tests were not available at the time), in his newly transplanted bone marrow from his sister, an unmatched bone marrow donor.

AUTISM

Severe disorder from an array of the Autism Spectrum Disorders (ASD)

Another common form of ASD is Asperger Syndrome

Developmental disorder affects parts of brain, notably the amygdala {are almond-shaped groups of nuclei located deep and medially within the temporal lobes of the brain}, hippocampus{plays important roles in the consolidation of information from short-term memory to long-term memory},and cerebellum › immune system, and gastrointestinal tract

1 out of 150 people are affected

More prevalent in males than in females.

…CHARACTERISTICS OF AUTISM

difficulties with social interaction

problems with verbal and nonverbal communication

repetitive behaviors or narrow, obsessive interests

behaviors can range in impact from mild to disabling.

…CAUSES OF AUTISM

• Complex,polygenic and multifactoral

– Highly heritable

– Gene-environment interaction

• Vaccines.

FUTURE TREATMENTS • Stem Cells

• Gene Therapies

• Advanced IVF Techniques

• Therapeutic Cloning

..ADULT STEM CELLS

•Stem cell collected from adult

can be harvested from many area

including the bone marrow.

•Alternative to Embryonic Stem

cells

•Potential to reverse and cure

Diabetes

..EMBRYONIC STEM CELLS

•Use undifferentiated cell from

embryos and cultures them to

grow into need cells

•Many ethical and social concerns

surrounding this research

•Neurons Grown from Embryonic

Stem Cells Restore Function in

Paralyzed Rats

•Hold potential cures for 1000s of

diseases many genetic disorders.

Advanced IVF Techniques

•This treatment is aimed at

women who would pass on a

genetic defect to the child.

•Also helps women who suffer

with mitochondria disease.

•Faulty genes are removed from

the embryo , and replaced by

healthy genes from the

additional woman.

..Therapeutic Cloning

•Using stem cells to replace

or create tissues and organs

•Currently heart tissues and

full bladders are being grow

in lab

Fig. Stem cell treatments and

tissues recreated in the heart

of a child