Heredity

Genetics The study of the mechanism of heredity Genetics will play a critical role in medicine in the future due to the Human Genome Project We now have the sequence of human DNA The next step will be to look at that DNA and understand the genes within Already, genetic testing may be influencing your life (beyond if you commit a crime ) My wife was tested, unknowingly, for CF carrier when she was pregnant with out second child. It turned out she is a carrier. Who knows how many other things they tested for but did not bother telling us because only the CF was relevant. We found out she is a carrier and that sort of blew my mind given that I had done research on CF. I would probably still do research on CF if I would have known that my grandkids could have CF.

What is genetics? The term "genetics" is derived from the word “gene". Recall that… All DNA is grouped into 46 chromosomes (23 pairs) A chromosome is a collection of genes A gene is a collection of triplets A triplet is a DNA code for a particular amino acid A chain of amino acids forms a polypeptide So, essentially genes tell our cells which proteins to make.

Genes The protein coded for by a gene may create a particular heritable trait. i.e. blood type, hair color, eye color etc. The protein may make an ion channel, an enzyme, a structure, etc.

Mutated Genes = Mutated Proteins Muscular Dystrophy Cystic Fibrosis Achondroplasia PKU Black Plague/AIDS Normal MD

There are many ways to mutate a protein

Genes Fair Skin??? Green Eyes???

Alleles Alleles: You have two copies of each gene. Each copy is called an allele.

Alleles Represent Separate Genes In the case of eye color, you may have an allele to make pigment (brown here) or you may lack pigment (blue eyes). Blue eyes allele Brown eyes allele

Alleles Matched genes at the same locus on homologous chromosomes Homozygous – two alleles controlling a single trait are the same Alleles are given letter names, for example the allele for eye color is B. Someone homozygous brown eyed is BB Heterozygous – the two alleles for a trait are different Someone heterozygous is Bb (where the little b designates a gene that codes for another color.

Alleles Brown is dominant so the person will have brown eyes Dominant – an allele masks or suppresses the expression of its partner Designated by capital letters Recessive – the allele that is masked or suppressed Recessive traits are only expressed if both alleles carry the recessive gene. Designated by lower-case letter.

Eye Color http://www.ideum.com/genetics-eyecalculator.html

Genotype and Phenotype Genotype – the genetic makeup Phenotype – the way one’s genotype is expressed The phenotype is brown eyes The genotype could BB or Bb

Transition

Randomizing the Gene Pool At this point we understand alleles, so next we will go into how these alleles are mixed up as they are passed on to offspring. Three things randomize how alleles make it into offspring. Independent assortment during meiosis Crossing over prior to meiosis Random fertilization (only one egg/sperm wins)

Why Randomize? The American Elm is subject to Dutch Elm Disease. The Siberian is less susceptible. HIV/Black Plague 10% of Europeans are resistant to AIDS because they have a genetic mutation that also provided resistance to Bubonic plague. The Cheetah People carrying a particular genetic mutation, known as CCR5-delta32, are known to remain AIDS-free, despite exposure to HIV. The mutation prevents the HIV virus from entering the cells of the immune system. The new theory suggests that the CCR5 mutation was a by-product of the European plagues. The proportion of people carrying the natural resistance rises dramatically in Europe and particularly Scandinavia, where the figure is 14-15 per cent.

1. Independent Assortment During Meiosis Chromosomes are randomly distributed to daughter cells Members of the allele pair for each trait are segregated during meiosis

1. Independent Assortment During Meiosis Chromosomes are randomly distributed to daughter cells Members of the allele pair for each trait are segregated during meiosis

1. Independent assortment during meiosis (cont.) The number of different types of gametes can be calculated by this formula: 2n, where n is the number of homologous pairs In a man’s testes, the number of gamete types that can be produced based on independent assortment is 223, which equals 8.5 million possibilities If you had 23 bags, each with a pair of chromosomes, and went down the line selecting one chromosome of the pair, there are 8.5 million different combinations.

2. Crossing over prior to meiosis Early in meiosis, chromosomes will actually swap genes.

2. Crossing over prior to meiosis If two genes are far apart, they are distributed randomly. Some genes are not far apart, say hair color and skin fairness, so redheads usually have fair skin.

Why cross over?

3. Random fertilization (only one egg/sperm wins) A single egg is fertilized by a single sperm in a random manner Considering independent assortment and random fertilization, an offspring represents one out of 72 trillion (8.5 million  8.5 million) zygote possibilities

transition

Genetics How then do we figure out what are the likely mixes of alleles we can have. The best tool is the Punnet square.

Modes of Inheritance There are three main types of inheritances Autosomal Dominant Autosomal Recessive X- linked (sex-linked) X- linked indicates a gene on the X chromosome. Sex linked genetics are different because there are not a pair of identical chromosomes. Autosomal indicates a gene on any chromosome other than X. The next few slides show the basics.

Dominant If the dominant gene is possessed, the phenotype is seen.

Recessive Recessive genes must be homozygous to show the phenotype

X-linked In males, the mutation is seen. In females, the mutation is subject to dominance/recessive

Dominant-Recessive Inheritance Examples of dominant disorders: achondroplasia (type of dwarfism) and Huntington’s disease Examples of recessive conditions: albinism, cystic fibrosis, and Tay-Sachs disease Carriers – heterozygotes who do not express a trait but can pass it on to their offspring

Incomplete Dominance Heterozygous individuals have a phenotype intermediate between homozygous dominant and homozygous recessive Sickling gene is a human example when aberrant hemoglobin (Hb) is made from the recessive allele (s) SS = normal Hb is made Ss = sickle-cell trait (both aberrant and normal Hb is made) ss = sickle-cell anemia (only aberrant Hb is made)

Multiple-Allele Inheritance B A Multiple-Allele Inheritance Genes that exhibit more than two alternate alleles ABO blood grouping is an example Three alleles (IA, IB, i) determine the ABO blood type in humans IA and IB are codominant (both are expressed if present), and i is recessive

ABO Blood Groups

Blood Allele Distributions: Just for Interest A B O Blood Allele Distributions: Just for Interest

Blood Allele Distributions: Just for Interest: A Type

Blood Allele Distributions: Just for Interest: B Type

Blood Allele Distributions: Just for Interest: O Type

Polygene Inheritance Depends on several different gene pairs at different loci acting in tandem Results in continuous phenotypic variation between two extremes Examples: skin color, eye color, and height

Polygenic Inheritance of Skin Color

We still don’t know it all. Just when people thought they had it down, along came chromosome 15 deletions. Prader-Willi syndrome if mutations is inherited from the father obesity, mental retardation, short stature. (abbreviated PWS) Angelman syndrome if mutation is inherited from the mother uncontrollable laughter, jerky movements, and other motor and mental symptoms. (abbreviated AS) During gametogenesis, certain genes are methylated and tagged as either maternal or paternal Developing embryos “read” these tags and express one version or the other

PWS Mouse model PWS AS Mouse model AS

We still don’t know it all.

Extrachromosomal (Mitochondrial) Inheritance Some genes are in the mitochondria All mitochondrial genes are transmitted by the mother Unusual muscle disorders and neurological problems have been linked to these genes

Genetic Screening, Counseling, and Therapy Newborn infants are screened for a number of genetic disorders: congenital hip dysplasia, imperforate anus, and PKU Genetic screening alerts new parents that treatment may be necessary for the well-being of their infant Example: a woman pregnant for the first time at age 35 may want to know if her baby has trisomy-21 (Down syndrome)

Carrier Recognition Identification of the heterozygote state for a given trait Two major avenues are used to identify carriers: pedigrees and blood tests Pedigrees trace a particular genetic trait through several generations; helps to predict the future Blood tests and DNA probes can detect the presence of unexpressed recessive genes Sickling, Tay-Sachs, and cystic fibrosis genes can be identified by such tests

Pedigree Analysis Cystic fibrosis: Autosomal recessive.b. Down syndrome: In most cases, Down syndrome is not a heritable condition, although there are some rare forms that can be inherited.c. Hemophilia: X-linked recessive. Particularly well known for being a disease present in the European royal families descended from Queen Victoria of England.d. Lyme disease: Lyme disease is an infectious disease, not a heritable disease.e. Sickle cell anemia: Autosomal recessive. An individual must inherit two defective copies of the gene to have an anemic phenotype. Thus, the disease is considered recessive. However, individuals inheriting one copy of the disease allele do have slightly affected red blood cells, sometimes referred to as the sickle cell trait. It is an interesting example of how the concept of dominance and recessiveness depends on the frame of reference.f. Tay-Sachs disease: Autosomal recessive.g. Familial adenomatous polyposis (FAP): FAP behaves like an autosomal dominant disease. However, the mutation is a loss-of-function mutation and therefore should be recessive. The reason that it behaves like a dominant disease is that in heterozygotic individuals, the chance of developing a mutation in the normal gene is high enough that it is likely to happen during their lifetimes. Individuals have inherited a single defective form of the gene, but their normal copy of the gene eventually mutates in one of their colon cells, resulting in FAP. This shows how the observed pattern of dominant and recessive traits does not necessarily match the underlying molecular genetics. Discussed in Lectures One and Two.h. Huntington disease: Autosomal dominant.i. Duchenne muscular dystrophy: X-linked recessive.j. Red-green color blindness: X-linked recessive.k. Spinocerebellar ataxia type 1 (SCA1): Autosomal dominant. Discussed in Lecture Three.

Fetal Testing Is used when there is a known risk of a genetic disorder Amniocentesis – amniotic fluid is withdrawn after the 14th week and sloughed fetal cells are examined for genetic abnormalities Chorionic villi sampling (CVS) – chorionic villi are sampled and karyotyped for genetic abnormalities

Fetal Testing

Genetic Testing Now Chromosome Studies Pedigree and karyotyping DNA Studies (indirect and direct) Sequence the gene or a part of the gene Protein Truncation studies See if the protein is too small Biochemical testing Test to see if there is a physiological impairment.

Human Gene Therapy Genetic engineering has the potential to replace a defective gene Defective cells can be infected with a genetically engineered virus containing a functional gene The patient’s cells can be directly injected with “corrected” DNA

Mutation Change in a gene or chromosome Causes an abnormal trait A mutation is a change in a gene or chromosome. It will cause an abnormal trait.

Mutagen Agent that causes mutations Cigarette smoke Pesticides X-rays Ultraviolet light Nuclear radiation A mutagen is an agent that causes mutations. There are numerous mutagens in cigarette smoke. Pesticides are mutagens. X-rays, ultraviolet light and nuclear radiation are also mutagens. Most mutagens are also carcinogens or cancer causing agents.

Mutations If there is an error in the DNA, that error may be seen as a mutation. There are three main types of mutation. Loss of function Tay-Sachs, PKU, Niemin-Pick's Partial loss of function Cystic fibrosis and sickle-cell anemia Gain of function (and that may not be good) Make too much of something as in epilepsy

Aneuploidy Mutations involve changes in single genes. Aneuploidy is when extra-chromosomes exist in the genome because of errors during meiosis.

Trisomy 21 Down Syndrome This is a karyotype for a person with an abnormal number of chromosomes. The have three copies of chromosome 21 because of nondisjunction in of the parents.

Maternal Age & Down Syndrome This slide shows the correlation of Down syndrome with the age of the mother. Paternal age is also a factor but it is not as strongly correlated as the age of the mother.

Down Syndrome Large tongue Flat face Slanted eyes Single crease across palm Mental retardation Some are not People with Down syndrome have a large tongue which often causes them have an open mouth. Their face is flat and the eyes are slanted. The palm of the hand has a single crease. Some individuals with Down syndrome are retarded but others are not.

Trisomy 18 Edward Syndrome Trisomy 18 is also known as Edward syndrome.

Edward Syndrome Heart defects Displaced liver Low-set ears Abnormal hands Severe retardation 98% abort Lifespan < 1 year Characteristics of Edward syndrome include heart defects, displaced liver and low-set ears. The hands have an unusual shape as shown on this slide. These individuals have severe retardation. Most of them abort before they are born. Those few who are born have a lifespan of less than one year.

Trisomy 13 Patau Syndrome Trisomy 13 or Patau syndrome is illustrated here.

Patau Syndrome Cleft lip and palate Extra fingers & toes Defects polydactylism Defects Heart Brain Kidneys Most abort Live span < 1 month A cleft lip and palate are present in this condition. If you count the fingers on this baby you will find there are six digits. Polydactylism refers to extra digits. Defects of the heart, brain and kidneys are also present in this condition. Most individuals with this condition abort. Those babies that do survive live less than one month. The baby in this picture was stillborn.

Klinefelter Syndrome Klinefelter syndrome results from an abnormal number of sex chromosomes. People with Klinefelter syndrome have a y chromosome so they are males. Having an extra X will cause them to have some feminine traits.

Klinefelter Syndrome Breast development Small testes Sterile Low intelligence Not retarded They may exhibit slight breast development. Small testes and sterility is another characteristic of Klinefelter syndrome. They often have lower intelligence but are not retarded. Click on the link for the Klinefelter website to read about people with this condition.

Turner Syndrome Having only one X chromosome causes Turner syndrome. These individuals are females.

Turner Syndrome Short Not go through puberty Produce little estrogen Sterile Extra skin on neck Girls with Turner syndrome are short and do not go through puberty. The reason they do not is because they produce little estrogen. It takes two X chromosomes to produce a normal amount of estrogen. Most individuals with Turner syndrome are sterile. An unusual characteristic is extra skin on the neck. The girl in this picture is 18, but has not gone through puberty.

Crosses Be able to cross any combination of homozygotes and heterozygotes with dominant, recessive, and sex-linked mutations.

If the mutation is dominant Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know If the mutation is dominant BB Bb bb BB x BB BB x Bb BB x bb Bb x Bb bb x Bb Bb x bb bb x bb BB Bb bb

If the mutation is dominant Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know If the mutation is dominant

Crosses to Know: Just a Start Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know: Just a Start If the mutation is dominant BB bb 4 BB 4 Brown Bb B B BB B BB BB B BB BB B b Bb 1 BB: 2 Bb : 1 bb 4 3 brown: 1 blue B BB Bb b Bb bb bb

Crosses to Know: Just a Start Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know: Just a Start If the mutation is dominant

If the mutation is recessive Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know If the mutation is recessive BB Bb bb BB x BB BB x Bb BB x bb Bb x Bb bb x Bb Bb x bb bb x bb BB Bb bb

If the mutation is recessive Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know If the mutation is recessive

If the mutation is recessive Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know If the mutation is recessive

Crosses to Know Sex – linked Crosses XX XhX XhXh XX x XY XhX x XY Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know Sex – linked Crosses XX XhX XhXh XX x XY XhX x XY XhXh x XY XX x XhY XhX x XhY XhXh x XhY XY XhY

Crosses to Know Sex – linked Crosses Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know Sex – linked Crosses

Crosses to Know Sex – linked Crosses Know: What the genotypes are and their ratios, what the phenotypes are and their ratios Crosses to Know Sex – linked Crosses

A man & woman are both carriers (heterozygous) for albinism A man & woman are both carriers (heterozygous) for albinism. What is the chance their children will inherit albinism? A man and a woman are both carriers for albinism. What is the chance their children will inherit albinism?

AA = Normal pigmentation Aa = Normal pigmentation (carrier) aa = Albino Man = Aa Woman = Aa A A The man will produce sperm cells by meiosis. During this process the alleles will separate into different sperm cells. He can make two different kinds of sperm cells. One kind will have the A allele and the other the a allele. The same is true of the woman when she produces an egg.   a a

A a A Aa AA One way to determine every combination of the man’s sperm cells and woman’s eggs is to align them on a square. It is called a Punnent square. *Each box of the square will receive an allele from one sperm and one egg. *AA will go in the box in the upper left. *The next square will receive the A allele from the sperm and the a allele from the egg. *Filling in each box will give every possible combination of eggs and sperms from a given couple.* a Aa aa

Genotypes Aa AA Phenotypes Aa aa Probability 1 AA, 2Aa, 1aa 3 Normal 1 Albino Aa aa Probability There is a lot of information we can derive from the Punnent square. The possible genotypes of the couple’s offspring are 1AA, 2Aa and 1aa out of four. Phenotypes are 3 normal and 1 albino out of 4. The probability of albinism is 1 out of 4 or 25%. 25% for albinism

A man & woman are both carriers (heterozygous) for PKU disease A man & woman are both carriers (heterozygous) for PKU disease. What is the chance their children will inherit PKU disease? Can you solve this problem for PKU disease?

P PP Pp P PP = Normal Pp = Normal (carrier) pp = PKU disease p p pp Set up the Punnent square as shown in this slide. *The letters in the boxes are these p

Genotypes Pp PP Phenotypes Pp pp Probability 1 PP, 2Pp, 1pp 3 Normal (2 carriers) 1 PKU disease Pp pp Probability This slide illustrates the possible genotypes, phenotypes and probability for PKU in the couple’s offspring. 25% for PKU disease

A man with sickle cell anemia marries a woman who is a carrier A man with sickle cell anemia marries a woman who is a carrier. What is the chance their children will inherit sickle cell anemia? Can you solve this problem for sickle cell anemia?

S ss Ss SS = Normal Ss = Normal (carrier) ss = Sickle Cell s s s The Punnent square will look like this. *The genotypes of the offspring are in the Punnent square. s

Genotypes ss Ss Phenotypes Probability 2 Ss, 2ss 2 Normal (carriers) 2 Sickle cell Probability Genotypes, phenotypes and probability are shown on this slide. 50% for Sickle cell

A man with heterozygous dwarfism marries a woman who has normal height A man with heterozygous dwarfism marries a woman who has normal height. What is the chance their children will inherit dwarfism? Dwarfism is dominant. Try this problem for dwarfism. See if you can work it before advancing to the next slide.

d D Dd dd DD = Dwarf Dd = Dwarf dd = Normal d d The Punnent square will look like this. *Here is the completed Punnent square. d

Genotypes Dd Dd Phenotypes dd dd Probability 2 Dd, 2dd 2 Normal 2 Dwarfs dd dd Probability Genotypes, phenotypes and the probability of dwarfism for this problem are illustrated on this slide. 50% for Dwarfism

X-linked Recessive Traits Alleles are on the X chromosome Inheritance pattern different in males and females X-linked recessive traits have their alleles on the X chromosome. The inheritance pattern is different in males than females.

XH Xh = Normal Female (Carrier) Xh Xh = Hemophilic Female XHy = Normal Male Xhy = Hemophiliac Male If a woman has one h allele she will not have hemophilia because a dominant H will enable her to produce clotting factors. A woman would have to have two h alleles to inherit hemophilia. However, a male only needs one h allele to have hemophilia.

A man with hemophilia marries a normal woman who is not a carrier A man with hemophilia marries a normal woman who is not a carrier. What is the chance their children will inherit hemophilia? Hemophilia is X-linked recessive. Be sure you write the alleles for hemophilia on the X chromosome to solve this problem.

XH XH Xh XH Xh XH Xh XHy XHy Xh XH = Normal Female XH Xh = Normal Female (Carrier) Xh Xh = Hemophilic Female XHy = Normal Male Xhy = Hemophiliac Male XH XH Xh XH Xh XH Xh It is always a good idea to write down every possible genotype and their corresponding phenotypes before you try to solve a genetics problem. Here are the genotypes for this problem. **** XHy y XHy

XH XH Xh XH Xh XH Xh XHy XHy Genotypes Phenotypes y Probability 2 Carrier Females 2 Normal Males XHy y XHy Probability Note that all the females are carriers and that none of males inherit hemophilia from their father. O% for Hemophilia

A normal man marries a normal woman who is a carrier for hemophilia A normal man marries a normal woman who is a carrier for hemophilia. What is the chance their children will inherit hemophilia? See if you can work this problem before advancing to the next slide. The most common type of hemophilia is linked to a mutation that occurred in Queen Victoria

XH Xh XH XH XH XH Xh XHy Xhy Xh XH = Normal Female XH Xh = Normal Female (Carrier) Xh Xh = Hemophilic Female XHy = Normal Male Xhy = Hemophiliac Male XH Xh XH XH XH XH Xh XHy Xhy Your Punnent square should look like this. * y

XH Xh XH XH , XH Xh, XHy, Xhy XH XH XH XH Xh XHy Xhy Genotypes Phenotypes 2 Normal Females (1 carrier) 1 Normal Males 1 Male Hemophiliac XHy y Xhy The chance for hemophilia in a girl for this problem is 0%. One of the two boxes for boys has hemophilia. Therefore the change of hemophilia is 50% if the child is a boy. Probability 50% for Male Hemophilic 0% for Female Hemophilic

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