GENETICS Genetics is the study of genes Genes; sequences of DNA. Genes are packaged together as

chromosomes and are passed from parent to offspring.

It is our genes that determine who we are and how we function at the most basic cellular level. Sometimes mistakes (mutations) cause significant disability or death, or benefits.

Genes; 25,000 genes.

GENETICS Study of hereditary, the passing of traits

from parents to their children. Physical traits such as eye color are

inherited as well as biochemical and physiologic traits, including the tendency to develop certain diseases.

Transmitting an inheritance Inherited traits are transmitted from parents

to offspring through genes in gametes (ova, and sperms).

A person’s genetic makeup is determined at fertilization, when ovum and sperm are united.

Chromosomes

In the nucleus of each germ cell are structures called chromosomes.

Chromosomes are made up of molecules of DNA, complexed with proteins called histones.

Chromosomes together carry the genetic blueprint of an individual.

DNA is a long molecule that’s made up of thousands of segments called genes.

Each of the traits that a person inherits is coded in their genes.

All human somatic (body) cells contain 23 pairs of chromosomes, one pair from each parent, for a total of 46 chromosomes. Each human sex cell, an egg or a sperm, contains 23 unpaired chromosomes.

PASS IT ON There are two genes for each trait that a person

inherits. One gene may be more influential (dominant) than the other(recessive) in developing a specific trait.

For example, a child may receive a gene for brown eyes from one parent and a gene for blue eyes from the other parent. The gene for brown eyes is dominant. Therefore, the child is more likely to have brown eyes.

A variation of a gene and the trait it controls is called an allele. When two different alleles are inherited, they’re said to be heterozygous. When the alleles are identical, they’re termed homozygous. A dominant allele may be expressed when it’s carried by only one of the chromosomes in a pair. A recessive allele is not expressed unless recessive alleles are carried by both chromosomes in a pair.

GENE XX (OR XY)

Of the 23 pairs of chromosomes in each living human cell, 22 pairs are somatic; they’re called autosomes. The gender is determined by the two sex chromosomes. Females have two X chromosomes. Males have one X chromosome and one is a smaller chromosome Y.

Each gamete produced by a male contains either an X or a Y chromosome. X+X= femaleX+X= male

GENE ACTIVATION

Although each somatic cell contains the same 23 pairs of chromosomes, only certain genes are activated in any given cell; therefore, only certain proteins or enzymes are produced by that cell.

Which genes are activated in which cell is determined during embryologic development and throughout life by circulating growth factors, hormones, and chemical produced by a given cell and its neighboring cells.

CELLULAR REPRODUCTION All cells reproduce during embryonic

development, which allows for growth of the embryo and differentiation (specialization) of the cells making up tissues and organs.

After birth and throughout adulthood, many cells continue to reproduce.

Cells that reproduce throughout a lifetime include cells of the bone marrow, skin, and digestive tract.

Liver and kidney cells reproduce when replacement of lost or destroyed cells is required. Special cells, called stem cells, are capable of reproducing indefinitely.

Other cells, including nerve, skeletal muscle, and

cardiac muscle cells, do not reproduce significantly after the first few months following birth.

MEIOSIS Meiosis is the process during which germ cells of the

ovary (primary oocytes) or testicle (primary spermatocytes) give rise to mature eggs or sperm .

Meiosis involves DNA replication in the germ cell, followed by two cell divisions rather than one, which results in four daughter cells, each with 23 (unpaired) chromosomes.

In males, all four daughter cells are viable and continue to differentiate into mature sperm.

In females, only one viable daughter cell (egg) is formed; the other three cells become nonfunctional polar bodies.

During fertilization, genetic information contained in the 23 chromosomes of the egg joins with genetic information contained in the 23 chromosomes of the sperm. This results in an embryo with 46 total chromosomes (two pairs of 23).

An interesting phenomenon occurs during DNA replication in the first meiotic stage. At this time, pieces of DNA may shift between the matched chromosome pairs, in a process called crossing-over. Crossing-over increases the genetic variability of offspring, and is one reason why siblings within a family may vary considerably in genotype and phenotype.

GENOTYPE AND PHENOTYPE Precise genetic information carried in the

chromosomes of the offspring is termed the genotype. Physical representation of genetic information (tall or short, dark or light) is called the phenotype.

Genetic Testing (cytogenetics) Genetic testing, called cytogenetics, involves

looking at the overall structure and number of the chromosomes. Genetic testing can be performed on any cell of the body, but in children and adults it is usually done by withdrawing white blood cells in a venous blood sample. For prenatal testing, fetal cells may be gathered during the processes of amniocentesis, or during chorionic villi sampling.

AMNIOCENTESIS

Amniocentesis is performed by inserting a needle through the abdominal wall of a pregnant woman into the amniotic sac that surrounds the fetus.

Chromosomes present in the fluid sample are then cultured and tested for number and shape are analyzed for genetic integrity.

This test is usually done at approximately 16 weeks' gestation and results are available in approximately 2 weeks.

CHORIONIC VILLI SAMPLING Involves gathering cells of the chorion

(the outer border of the fetal membranes).

The cells are gathered by placing a needle through the abdomen or cervix between 8 and 12 weeks of pregnancy.

The cells do not need to be cultured, so the chromosomal analysis is available in approximately 1 to 2 days.

PATHOPHYSIOLOGIC CONCEPTS

Mutation:A mutation is a permanent change in genetic

material A mutation is an error in the DNA sequence.

Mutations can occur spontaneously, or after the exposure of a cell to radiation, certain chemicals, or various viral agents.

Most mutations will be identified and repaired by enzymes working in the cell.

If a mutation is not identified or repaired, or if the cell does not undergo programmed death, that mutation will be passed on in all subsequent cell divisions.

Mutations may result in a cell becoming cancerous.

MUTATION RESULTS

Mutations in the gametes (the egg or sperm) may lead to congenital defects in an offspring

Some mutations cause serious or deadly disorders

that occur in three different forms:

Single gene disorder

Chromosomal disorder

Multifactorial disorders

SINGLE GENE DISORDER Inherited in clearly identifiable pattern Two important inheritance patterns are

called autosomal dominant and autosomal recessive. Most hereditary disorders are caused by autosomal defects:

Autosomal dominantAutosomal recessive

Sex linked disorders

AUTOSOMAL DOMINANT

Male & female equally affected One parent is usually affected If one parent is affected, 50% of offspring is being affected

All offspring affected, if both parents are affected

Ex: Marfan syndrome

AUTOSOMAL RECESSIVE INHERITANCE

• Male and female are affected equally. • If both parents are unaffected but

heterozygous for the trait (carriers), each of their offspring has a one in four chance of being affected.

• If both parents are affected, all of their offspring will be affected.

• If one parent is affected and the other is not a carrier, all of the parents’ offspring will be unaffected but will carry the altered gene.

• If one parent is affected and the other is a carrier, each of the offspring will have a chance 50% of being affected and 50%of being a carrier

SEX-LINKED INHERITANCE

If the two parents are unaffected , each with an altered recessive gene (a) on an autosome. Each offspring will have 25% chance of being affected and 50% chance of being a carrier. Females:

homozygous for a disease allele, homozygous for a normal allele, or heterozygous. Males: a single X-linked recessive gene can cause

disease

Males are more commonly affected by X-linked recessive diseases than females.

CHROMOSOMAL BREAKS

During mitosis and meiosis, pieces of chromosomes may break off, be added inappropriately to other chromosomes, or be deleted entirely. If deletions or additions occur during meiosis in the egg or sperm, a congenital defect or death of the embryo may result.

If deletions or additions of chromosomes occur during mitosis, the affected cell line will usually die out.

ERRORS IN CHROMOSOME NUMBER

Nondisjunction During cell division, chromosomes

normally separate in a process called disjunction. Failure to do so—called nondisjunction— causes an unequal distribution of chromosomes between the two resulting cells. Gain or loss of chromosomes is usually due to nondisjunction of autosomes or sex chromosomes during meiosis.

ERRORS IN CHROMOSOME NUMBER

Any change from the normal human chromosome number of 46 chromosomes is called aneuploidy.

An aneuploidy in which there are only 45 chromosomes is called a monosomy.

An aneuploidy in which there are 47 chromosomes is called a trisomy. Having more than 47 chromosomes is possible but rare.

MONOSOMY If any chromosome other than the X or Y is

lost, the embryo will spontaneously abort.

However, the loss of one of the sex chromosomes may result in a viable offspring. Usually the Y chromosome is lost, resulting in 44 somatic chromosomes and one sex chromosome, for a total of 45 chromosomes (often expressed 45, X/O, to indicate no Y chromosome).

The resulting disorder is called Turner's syndrome. Monosomy of any chromosome is a major cause of spontaneous abortion in the first trimester

TRISOMY

A trisomy occurs when somatic or sex chromosomes do not separate properly during meiosis. This is called non-disjunction.

Most trisomies cause spontaneous abortion of the embryo, but rarely live births may result.

Trisomies that may result in live births include trisomies of the sex chromosomes and trisomies of chromosomes 8, 13, 18, and 21. Trisomy 21 is called Down syndrome

MIXED RESULTS Nondisjunction may occur during very early

cell divisions after fertilization and may or may not involve all the resulting cells.

A mixture of cells, some with a specific chromosome abnormality and some with normal cells, results in mosaicism. The effect on the offspring depends on the percentage of normal cells.

The incidence of nondisjunction increases with parental age, especially maternal age. Miscarriages can also result from chromosomal abnormality. Fertilization of an ovum with a chromosome aberration by a sperm with a chromosome aberration usually doesn’t occur.

TRANSLOCATION Chromosome break and rejoin in an

abnormal arrangement

Balanced, reserve genetic material Imbalanced, visible abnormalities (partial

monosomies / trisomies)

Translocation

Reciprocal translocation

Robertsonian translocation

MULTIFACTORIAL DISORDERS Genetic & environmental factors

(cleftlip/palate, spina bifida) maternal age • use of chemicals • maternal infections during pregnancy or

existing diseases in the mother • maternal or paternal exposure to radiation • maternal nutritional factors • general maternal or paternal health • other factors, including high altitude,

maternal-fetal blood incompatibility, maternal smoking, and poor-quality prenatal

care.

GENETIC DISORDERS

• multifactorial disorders (cleft lip and cleft palate)

• six single-gene disorders (cystic fibrosis, hemophilia, Marfan syndrome, phenylketonuria [PKU], sickle cell anemia)

• a chromosomal disorder (Down syndrome).

CONGENITAL DEFECTS

Also called birth defects, include genotypic and phenotypic errors occurring during embryogenesis and fetal development.

Some congenital defects, such as cleft palate and limb abnormalities, may be apparent at birth, whereas other congenital defects, such as an abnormal or absent kidney and certain types of heart disease, may not be recognized immediately.

Congenital defects may result from genetic mistakes made during meiosis of the sperm or egg, or from environmental insults experienced by the fetus during gestation.

TERMINOLOGY hereditary = derived from parents familial = transmitted in the gametes

through generations congenital = present at birth (not

always genetically determined - e.g. congenital syphilis, toxoplasmosis)

! not all genetical diseases are congenital - e.g. Huntington disease - 3rd to 4th decade of life

TERATOGENS Teratogens Teratogenesis is an error in fetal

development that results in a structural or functional deficit (e.g., a deficit in brain function).

Environmental stimuli that cause congenital defects are called teratogenic agents.

Teratogenic agents can lead to genetic mutations or errors in phenotype.

Common manifestations of teratogenic exposure include congenital heart disease, abnormal limb development, mental retardation, blindness, hearing loss, and abnormalities in growth.

OF THE TERATOGENIC AGENTS : Alcohol. TORCH Group of Teratogens

T stands for toxoplasmosis, R for rubella, C for cytomegalovirus, and H for the herpes simplex virus. The letter O stands for all other infections, especially syphilis,

hepatitis B, mumps, gonorrhea, and chickenpox. A newborn infected during gestation with any of the

TORCH group of MOs may show microcephaly, hydrocephaly, mental retardation, or loss of hearing or sight.

Congenital heart defects are common, especially with rubella.

Radiation exposure may increase the risk that the child will later develop cancer. *Whether an embryo or fetus will be affected by any teratogenic agent depends on several factors, which include the timing and dose of exposure, and maternal and paternal health and nutritional status.

TIMING OF EXPOSURE TO A TERATOGEN - Teratogenic agents are most likely to cause structural

defects at the first trimester, however, the nervous system is always susceptible to a teratogen because it continues to develop even after birth.

- Infants exposed to an infectious agent in the third trimester or during the birth process are at increased risk of developing the disease. This is true for neonatal infection by hepatitis B virus or HIV.

Dose of a Teratogen - The dose of exposure is important in determining the

likelihood that a teratogenic agent will cause a congenital defect.

- Levels of radiation used in most diagnostic techniques or low concentrations of a drug may not produce any effect on the fetus.

- Higher doses of radiation or a drug may adversely affect the fetus

MATERNAL HEALTH AND NUTRITIONAL STATUS

Infants born to women with diabetes or seizure disorders are at higher risk of fetal anomalies, the latter perhaps due to the effects of both the seizures themselves and the medications used to treat the disorder.

Maternal diets low in folic acid have been associated with development of neural tube defects such as spina bifida..

DOWN SYNDROME

Down syndrome produces mental retardation, characteristic facial features, and distinctive physical abnormalities. It’s also associated with heart defects and other congenital disorders. Life expectancy and quality of life for patients with Down syndrome

have increased significantly because of improved treatment

of related complications and better developmental education programs.

CLINICAL MANIFESTATIONS - Variable levels of mental retardation.

- Upward slanting of the eyes.

- Short hands that have only one crease on the palm (a simian crease)

- low-set ears. - Short stature. - Protruding tongue.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 July 2005 09:03 PM)

©2005 Elsevier

Clinical Features of Down Syndrome

COMPLICATIONS Spontaneously abortion of about 20%

between 10 and 16 weeks' gestation. Congenital heart or other organ defects

are frequent . Risk of childhood leukemia is increased

in children with Down syndrome.

Premature senile dementia, similar to Alzheimer’s disease

Acute and chronic infections, diabetes mellitus, and thyroid disorders.

TURNER SYNDROME

Is a monosomy of the sex chromosomes. Infants born with Turner syndrome have 45 chromosomes: 22 pairs of somatic chromosomes and 1 sex chromosome, usually the X (45, X/O). This disorder is common in spontaneously aborted fetuses. Females with Turner syndrome lack ovaries.

Clinical Manifestations Clinical manifestations may be nonexistent, mild, or moderate and include: Short stature and webbing of the neck. Lack of secondary sex characteristics and amenorrhea .

Complications -Congenital heart defects may accompany the sex chromosome monosomy. -Increased risk of childhood bone fractures and adult osteoporosis due to lack of estrogen. -Some individuals may demonstrate signs of learning disability.

  Klinefelter Syndrome   Klinefelter syndrome is a polysomic disorder

characterized by one or more extra X chromosomes in a genotypic male (47, X/X/Y; 47, X/X/X/Y).. Klinefelter syndrome may result from non-disjunction of the male or female X chromosome during the first meiotic division, at approximately equal rates in males and females.

.

Clinical Manifestations Although the infant may appear normal at birth,

he may show a decrease in male secondary sex characteristics during puberty. Gynecomastia (breast enlargement) and other

female patterns of fat deposit. Infertility and sexual dysfunction. Tall stature in adult life because decreased

levels of testosterone do not contribute to epiphyseal bone plate closure.

Individuals may demonstrate reduced mental functioning, especially with increasing number of X chromosomes.

Thank you