The branch of Genetics which deals The branch of Genetics which deals with the inheritance of characters in with the inheritance of characters in Human is termed Human GeneticsHuman is termed Human Genetics

Human Genetics had its birth in 1901 Human Genetics had its birth in 1901 when Sir Archibald Garrod a British when Sir Archibald Garrod a British physician pointed out that inborn physician pointed out that inborn errors of metabolism like errors of metabolism like phenylketonuria are gene controlled phenylketonuria are gene controlled and are inherited in a simple and are inherited in a simple Mendelian fashionMendelian fashion

Methodologies used in genetics

Pedigree analysis Twin studies Genetic analysis of the biochemical

process Microscopic analysis of the

chromosome structure Direct analysis of the DNA

Pedigree analysis

One of most powerful tools in human genetic studies is pedigree analysis

A pedigree is a chart showing inheritance patterns in a family

Why do Pedigrees?Why do Pedigrees?

Punnett squares and chi-square tests work Punnett squares and chi-square tests work well for organisms that have large well for organisms that have large numbers of offspring and controlled numbers of offspring and controlled matings, but humans are quite different:matings, but humans are quite different:

1. small families. Even large human 1. small families. Even large human families have 20 or fewer children.families have 20 or fewer children.

2. Uncontrolled matings, often with 2. Uncontrolled matings, often with heterozygotes.heterozygotes.

3. Failure to truthfully identify parentage.3. Failure to truthfully identify parentage.

Pedigree AnalysisPedigree AnalysisBasic principlesBasic principles

If more than one individual in a family is If more than one individual in a family is afflicted with a disease, it is a clue that the afflicted with a disease, it is a clue that the disease may be inherited. disease may be inherited.

A doctor needs to look at the family A doctor needs to look at the family history to determine whether the disease history to determine whether the disease is indeed inherited and, if it is, to establish is indeed inherited and, if it is, to establish the mode of inheritance. the mode of inheritance.

This information can then be used to This information can then be used to predict recurrence risk in future predict recurrence risk in future generations.generations.

A basic method for determining the pattern of A basic method for determining the pattern of inheritance of any trait (which may be a inheritance of any trait (which may be a physical attribute like eye color or a serious physical attribute like eye color or a serious disease like Marfan syndrome) is to look at its disease like Marfan syndrome) is to look at its occurrence in several individuals within a family, occurrence in several individuals within a family, spanning as many generations as possible. spanning as many generations as possible.

For a disease trait, a doctor has to examine For a disease trait, a doctor has to examine existing family members to determine who is existing family members to determine who is affected and who is not. affected and who is not.

The same information may be difficult to obtain The same information may be difficult to obtain about more distant relatives, and is often about more distant relatives, and is often incomplete. incomplete.

Once family history is determined, Once family history is determined, the doctor will draw up the the doctor will draw up the information in the form of a special information in the form of a special chart or family tree that uses a chart or family tree that uses a particular set of standardized particular set of standardized symbols. symbols.

An example of a pedigree chart:

1. Generations are labeled with Roman numerals (I, II, III, IV, V,…)2. Children are written in birth order from left to right3. Any person can be identified by his or her generation and number, e.g.III4 (who in this example unwisely married her first cousin, III5)

Modes of transmission of disease alleles in pedigrees

A. There are six basic patterns of inheritance of disease alleles in humans

1. Autosomal recessive 2. Autosomal dominant 3. Xlinked recessive 4. Xlinked dominant 5. Ylinked 6. Mitochrondrial

Goals of Pedigree AnalysisGoals of Pedigree Analysis

1. Determine the mode of 1. Determine the mode of inheritance: dominant, recessive, inheritance: dominant, recessive, partial dominance, sex-linked, partial dominance, sex-linked, autosomal, mitochondrial, maternal autosomal, mitochondrial, maternal effect.effect.

2. Determine the probability of an 2. Determine the probability of an affected offspring for a given cross.affected offspring for a given cross.

Dominant and recessive Dominant and recessive traitstraits

Using genetic principles, the Using genetic principles, the information presented in a pedigree information presented in a pedigree can be analyzed to determine can be analyzed to determine whether a given physical trait is whether a given physical trait is inherited or not and what the pattern inherited or not and what the pattern of inheritance is.of inheritance is.

In simple terms, traits can be either In simple terms, traits can be either dominant or recessive. dominant or recessive.

DDominant traitominant trait A dominant trait is passed on to a son or daughter A dominant trait is passed on to a son or daughter

from only one parent.from only one parent. Characteristics of a dominant pedigree are: Characteristics of a dominant pedigree are:

1) Every affected individual has at least one affected 1) Every affected individual has at least one affected parent; parent;

2) Affected individuals who mate with unaffected 2) Affected individuals who mate with unaffected individuals have a 50% chance of transmitting the individuals have a 50% chance of transmitting the trait to each child; andtrait to each child; and

3) Two affected individuals may have unaffected 3) Two affected individuals may have unaffected

children. children.

Autosomal dominant

Features of autosomal dominant Features of autosomal dominant inheritance:inheritance:

Both males and females in Both males and females in approximately equal numbersapproximately equal numbers

Persons are affected in each Persons are affected in each generation and males can transmit generation and males can transmit the condition to males or females or the condition to males or females or vice versavice versa

Unaffected persons do not transmit Unaffected persons do not transmit the conditionthe condition

The pedigree given below shows The pedigree given below shows inheritance of dominant form of inheritance of dominant form of dwarfism known as achondroplasia. dwarfism known as achondroplasia. Individuals with this skeletal disorder Individuals with this skeletal disorder have an enlarged skull, short arms have an enlarged skull, short arms and legs, and can be diagnosed by and legs, and can be diagnosed by radiologic examination at birth.radiologic examination at birth.

I-1 and I-2 are having a child, what is the probability of the child having the acondroplasia phenotype?

•P(A_)= ½* 1= ½ •Note the affected males and females in each

generation, characteristic of a Mendelian autosomal dominant disorder.

Recessive traitRecessive trait

Recessive traits are passed on to Recessive traits are passed on to children from both parents, children from both parents, although the parents may seem although the parents may seem perfectly "normal." perfectly "normal."

Characteristics of recessive Characteristics of recessive pedigrees are: 1) An individual who is pedigrees are: 1) An individual who is affected may have parents who are affected may have parents who are not affected;not affected;

2) All the children of two affected 2) All the children of two affected individuals are affected; and individuals are affected; and

3) In pedigrees involving rare traits, 3) In pedigrees involving rare traits, the unaffected parents of an affected the unaffected parents of an affected individual may be related to each individual may be related to each other. other.

Recessive Autosomal Recessive Autosomal PedigreePedigree

The most typical features of The most typical features of autosomal recessive inheritance:autosomal recessive inheritance:

Disease is expressed in homozygoteDisease is expressed in homozygote The low risk to offspring The low risk to offspring Equal frequency and severity in each Equal frequency and severity in each

sex.sex.

Autosomal recessive Albinism is caused by an allele that codes for a defective

protein. The defective protein is insufficient for normal pigmentation only if the mutant allele is present in two copies, this situation is called haploinsufficiency.

The dominant allele A determines the ability to make pigment,

In albinos the synthesis of melanin is blocked.

A/A active enzyme pigmented

A/a active enzyme pigmented

a/a inactive enzyme albino

Molecular basis of albinism

Pedigree example: albinism

Autosomal polymorphisms

•Polymorphism: the existence of two or more common phenotypes of a character in a population. Often inherited in a standard Mendelian manner.•Human polymorphism examples include: widow’s peak vs none; attached vs free earlobes

Autosomal polymorphism

Human populations are dimorphic for the ability to taste a bitter chemical: phenylthiocarbamide (PTC)

•Is the allele that confers the ability to taste PTC dominant or recessive?

SEX LINKED INHERITANCESEX LINKED INHERITANCE

In case of sex linked inheritance the In case of sex linked inheritance the frequency of disease in females and frequency of disease in females and males is different. There are three males is different. There are three types of sex linked inheritance:types of sex linked inheritance:

X-linked dominantX-linked dominant X-linked recessiveX-linked recessive Y-linked inheritance (holandric)Y-linked inheritance (holandric)

X-linked inheritance X-linked inheritance

X-linked inheritance can be either X-linked inheritance can be either dominant or recessive, although in dominant or recessive, although in patients with a recessive X-linked patients with a recessive X-linked condition, the phenotype is usually condition, the phenotype is usually observed in the male observed in the male

X Y

A

Sex-Linked DominantSex-Linked Dominant

Mothers pass their X’s Mothers pass their X’s to both sons and to both sons and daughtersdaughters

Fathers pass their X to Fathers pass their X to daughters only.daughters only.

XXDD = dominant mutant = dominant mutant alleleallele

XXdd = recessive normal = recessive normal alleleallele

Sex-Linked RecessiveSex-Linked Recessive

males get their X from males get their X from their mothertheir mother

fathers pass their X to fathers pass their X to daughters onlydaughters only

females express it females express it only if they get a copy only if they get a copy from both parents.from both parents.

expressed in males if expressed in males if present recessive in present recessive in femalesfemales

Hemophilia is a genetic disorder passed Hemophilia is a genetic disorder passed from one generation to the next through from one generation to the next through the X (female) chromosome.  It is a the X (female) chromosome.  It is a disease in which the blood does not clot disease in which the blood does not clot normally, due to abnormalities in some normally, due to abnormalities in some blood proteins that cause clotting.  blood proteins that cause clotting.  People with hemophilia (hemophiliacs) People with hemophilia (hemophiliacs) have blood that clots very slowly.   They have blood that clots very slowly.   They are in constant danger of bleeding to are in constant danger of bleeding to death, even if they have a minor injury.   death, even if they have a minor injury.   Surgery or even dental work can also be Surgery or even dental work can also be very risky very risky

Although women transmit the disease, only Although women transmit the disease, only men can exhibit it.  Women who carry men can exhibit it.  Women who carry hemophilia (carriers) have the gene on one hemophilia (carriers) have the gene on one of their X of their X chromosomeschromosomes.  Since the gene is .  Since the gene is recessive, they do not have the disorder.  recessive, they do not have the disorder.  But if a male has the bad gene, then he will But if a male has the bad gene, then he will be a hemophiliac because there is no be a hemophiliac because there is no matching gene on his Y chromosome to be matching gene on his Y chromosome to be dominant to it.  Females must have the gene dominant to it.  Females must have the gene on both X chromosomes to have hemophilia. on both X chromosomes to have hemophilia. In the past, most hemophiliacs died young, In the past, most hemophiliacs died young, but today, they can be treated with blood but today, they can be treated with blood transfusions. The following is a chart of the transfusions. The following is a chart of the hemophilia trait in one family over two hemophilia trait in one family over two generations. generations.

Hemophilia is often called the disease Hemophilia is often called the disease of kings because it was carried by of kings because it was carried by many members of Europe’s royal many members of Europe’s royal family. family.

Queen Victoria of Queen Victoria of England was a England was a carrier of hemophilia carrier of hemophilia and passed the and passed the disease to many of disease to many of her descendants her descendants (including the (including the Russian emperor’s Russian emperor’s family and the family and the Spanish royal Spanish royal family). family).

Many people say Many people say that this played a that this played a small role in the small role in the downfall of the downfall of the Russian royal Russian royal family during the family during the Russian Russian RevolutionRevolution

The present British royal family The present British royal family escaped the disorder because Queen escaped the disorder because Queen Victoria’s son, king Edvard VII did not Victoria’s son, king Edvard VII did not inherit the defective alllele, and all inherit the defective alllele, and all the subsequent rulers of England are the subsequent rulers of England are his deacendants. Three of Victoria’s his deacendants. Three of Victoria’s nine children did receive the nine children did receive the defective allele. It is still being defective allele. It is still being transmitted to future generations transmitted to future generations through the royal families in Europe ( through the royal families in Europe ( except Russia)except Russia)

Y-linked inheritanceY-linked inheritanceHypertrichosisHypertrichosis

HHuntington’s disease is a hereditary brain untington’s disease is a hereditary brain disease which usually begins in mid-life disease which usually begins in mid-life (30-45). HD can affect all ethnic (30-45). HD can affect all ethnic backgrounds and both males and females backgrounds and both males and females are affected equally. Although are affected equally. Although Huntington’s is not as common as Huntington’s is not as common as hemophilia, about 30,000 Americans have hemophilia, about 30,000 Americans have the disease and 150,000 have a 50% the disease and 150,000 have a 50% chance of inheriting it. People with chance of inheriting it. People with Huntington’s disease can experience Huntington’s disease can experience personality change, depression, mood personality change, depression, mood swings, involuntary movements, slurred swings, involuntary movements, slurred speech, and difficulty in swallowing. As the speech, and difficulty in swallowing. As the disease progresses, the severity of disease progresses, the severity of symptoms increases. Concentration can be symptoms increases. Concentration can be diminished, walking and everyday diminished, walking and everyday activities become more difficult, and activities become more difficult, and involuntary movements are more severe. involuntary movements are more severe.

CCystic Fibrosis (CF) ystic Fibrosis (CF) is an inherited is an inherited disorder which disorder which affects many affects many functions of the functions of the body, such as body, such as breathing, digestion, breathing, digestion, and reproduction. It and reproduction. It is a lifelong disorder is a lifelong disorder which usually gets which usually gets more severe by age more severe by age and both male and and both male and females can have it. females can have it.

IIn CF, the glands which produce n CF, the glands which produce mucus, saliva and intestinal fluids do mucus, saliva and intestinal fluids do not work properly and people with not work properly and people with Cystic Fibrosis have secretions which Cystic Fibrosis have secretions which are thick and sticky rather than thin are thick and sticky rather than thin and watery. This can cause breathing and watery. This can cause breathing problems, lung damage, improper problems, lung damage, improper growth and weight gain, digestive growth and weight gain, digestive problems, and respiratory problems, problems, and respiratory problems, but people with Cystic Fibrosis have but people with Cystic Fibrosis have normal intelligence. normal intelligence.

SSickle cell anemia is a ickle cell anemia is a group of inherited red group of inherited red blood cell disorders. blood cell disorders. Sickle red blood cells Sickle red blood cells are hard and sticky, are hard and sticky, unlike normal red unlike normal red blood cells which are blood cells which are round, like doughnuts. round, like doughnuts. People get sickle cell People get sickle cell anemia at birth by anemia at birth by inheriting an abnormal inheriting an abnormal hemoglobin from both hemoglobin from both parents who may be parents who may be carriers of the sickle carriers of the sickle cell trait or have the cell trait or have the disease. Hemoglobin disease. Hemoglobin