Genetics

Genetics

• A few facts about inheritance known since ancient times:– children resemble their

parents. – Domestication followed by

selective breeding to improve plants and animals. Mostly 10-12,000 years ago.

– Some lines are true-breeding, others have a variety of offspring types. Different breeds can be produced through selective breeding.

Some Older, Incorrect Theories• Hippocrates, an ancient Greek, taught the

idea of pangenesis, that inheritance comes from the presence in each organ of tiny replica organs. These replicas moved through the blood to the semen, where they formed a tiny human which grew in its mother’s womb. Problem: if you cut off someone’s arm, their children still have arms.

• Preformation is the idea that each sperm contains a miniature person: development is merely a process of enlarging and maturing the person already present in the sperm cell. There is another version of this theory that puts the miniature person in the egg instead of the sperm.

• Inheritance of acquired characteristics. The idea that events that occur in your life affect your offspring directly. For instance, constant stretching of the giraffe’s neck made its offspring’s neck longer. Often associated with Lamarck, but the idea is much older.

More Ancient Ideas• Relative contribution of male and

female. Many cultures believed that the child grew from the semen, with the female’s role merely to act as a source of nutrition, like planting a seed in the garden. Also, allegedly some New Guinea cultures didn’t know that sex was necessary for reproduction, which implies the female was the sole source of the child.

• Blending inheritance. Like mixing red paint with white paint: the results is pink paint, and there is no way to ever separate out the red and white.

• Plants and sex. Although it was known to many ancient cultures, the idea that all plants have male and female parts wasn’t widely accepted until the early 1700’s.

Mendel• Gregor Mendel lived in what is now the Czech

Republic (then part of the Austria-Hungarian Empire) from 1822 to 1884

• After high school he became a monk. The monastery sent him to the University of Vienna.

• After college he did plant hybridization experiments in the monastery garden, growing more than 28,000 pea plants between 1856 and 1863.

• Wrote up the work as “Experiments on Plant Hybridization” in a local scientific journal, where it was promptly forgotten. In those days, Darwin’s work was stirring controversy. Darwin had an incorrect notion of genetics: evolution was reconciled with genetics in the 1930’s, in the “modern synthesis”.

• Mendel was elected abbot and gave up his studies, dying in 1884.

• In 1900, 3 scientists working on plant breeding independently found his paper, read it, and understood how it explained their own work: the “rediscovery” of Mendel. This is the start of modern genetics.

Mendel’s Basic Innovations• Inheritance is particulate: genes are

not blended together, even if the effects of the genes get blended. For instance, in some plants if you cross a red flower with a white flower, the offspring have pink flowers. But, if you then cross 2 of the pink flowers together, the next generation has some red flowers and some white flowers, unchanged by having been in a pink parent.

• Counting offspring, and seeing experimental numbers as imperfect reflections of underlying simple ratios. As an example, if you flipped a coin 1000 times you might get 477 heads and 523 tails. This represents a 1:1 ratio that contains a small amount of random error.

Mendel’s Experiments• He worked with pea plants. Peas

have male and female parts all within one flower. You can take the pollen (male gamete, equivalent to sperm) and put it on the pistils (female structures) of another plant, where it fertilizes the ovule (female gamete) to form a zygote, the first cell of the next generation.

• Peas can self-pollinate (or “self”): the male pollen can fertilize the female ovule within a single plant. This is the closest possible genetic relationship.

• He worked with true-breeding lines: all peas within the line looked similar.

• He started with 7 different true-breeding lines, which differed for 7 distinct characters.

Examining One Trait• Start with flower colors: one line has

purple flowers, another line has white flowers. These two lines are called the “P generation”, for parental. When crossed, their offspring are the F1 generation. All of the F1 offspring are purple. Purple is called the dominant trait, because it is expressed in the F1 offspring. White is recessive, not expressed in the F1 offspring.

• When the F1 plants are self-pollinated (or crossed with each other), their offspring are the F2 generation. The F2 are the grandchildren of the P generation. The F2 were found in a ratio of ¾ purple to ¼ white.

• The same effects were seen for all 7 traits: if two lines are crossed together, the F1 all look like one of the parents, and the F2 are ¾ like one parent (the dominant trait) and ¼ like the other parent (the recessive trait).

Explanation and Vocabulary• Genes are the factors that control the inherited traits. Genes are made of DNA; they

are part of the chromosomes.• Individual versions of a gene are called alleles. Here, the flower color gene has two

alleles: a purple allele and a white allele. • Pea plants (and humans and most higher organisms) are diploid: they have 2 copies

of each gene, one from each parent. The gametes (sperm and egg, or pollen and ovule) are haploid: only 1 copy of each gene.

• When the sperm fertilizes the egg, the two haploid genomes mix, forming a new diploid, which is the zygote, the first cell of the offspring.

• The true breeding purple line produces only pollen carrying the purple allele, and all the ovules from the true-breeding white line have the white allele. The true breeding lines are homozygotes: the two copies of the flower color gene in each plant are identical. True breeding is the same as homozygous.

• So, when pollen from a purple flower fertilizes ovules from a white flower, the F1 offspring gets one purple allele and one white allele. It is a heterozygote: the two copies of the gene are different. “Hybrid” is the same as heterozygous.

• In the heterozygote, the dominant allele is expressed and the recessive allele is not expressed. The heterozygote looks just like the dominant homozygote. The genotype of the plants-- their genetic constitutions-- are different (one is a homozygote and one is a heterozygote), but their phenotype--their physical appearance– is the same: purple flowers.

More Explanation

More Explanation• P is the symbol we will use for the

purple allele.• p is the symbol for the white allele.

Both alleles are different versions of the flower color gene.

• Since peas have 2 copies of each gene (diploid), a pea plant can be PP, Pp, or pp.

• The parental plants, from true breeding lines, are homozygous: PP (purple) and pp (white).

• PP parents can only make P gametes, and pp parents can only make p gametes.

• The P pollen fertilizes the p ovule, producing the diploid Pp F1 offspring.

• The Pp plants are purple, because P is dominant and p is recessive.

• The homozygous PP plants and the heterozygous Pp plants are both purple: they have different genotypes (genetic constitutions) but the same phenotype (physical appearance).

Still More Explanation• The F1 heterozygotes are Pp. Half of the

gametes they make are P and the other half are p.

• When the F1 plants are self-pollinated, both the male and the female parts make P and p gametes.

• Fertilization is random, so there are 4 possibilities:

• 1. P pollen fertilizes a P ovum, giving PP zygote

• 2. P pollen fertilizes a p ovum, giving Pp zygote

• 3. p pollen fertilizes a P ovum, giving Pp zygote

• 4. p pollen fertilizes a p ovum, giving pp zygote.

• Adding these up, ¼ of the offspring are PP, ½ are Pp, and ¼ are pp.

• Phenotypes: PP and Pp are purple, so ¾ purple. Pp is white, so ¼ white.

• The Punnett square is a simple way of combining gametes and seeing the genotypes of the next generation.

Cross Summary

• Mendel’s Law of Segregation: Diploids produce equal numbers of gametes from each allele. The gametes combine at random to produce the next generation.

Back Cross• So far we have seen what happens when two

homozygotes are crossed (all the offspring are heterozygotes), and what happens when two heterozygotes are crossed (genotype ratio of ¼ PP, ½ Pp, ¼ pp; phenotype ratio of ¾ purple to ¼ white).

• One other possibility: crossing a heterozygote to a homozygote. This is called a backcross: an F1 heterozygote is crossed to one of the parental homozygotes.

• A backcross can be made to the dominant parental type or to the recessive parental type. A testcross is the latter type: crossing a heterozygote to a homozygous recessive parental type.

• In a backcross, the heterozygote (Pp) produces ½ P gametes and ½ p gametes. The homozygote produces only one kind of gamete, P or p.

• When the gametes combine, ½ are homozygotes and ½ are heterozygotes.

• If the backcross is to the dominant parent, all offspring show the dominant phenotype.

• If the backcross is to the recessive parent (a testcross), ½ the offspring have the dominant phenotype and ½ have the recessive phenotype.

Complications: Variations in Dominance

• All of Mendel’s traits had two alleles, a dominant allele (expressed in the heterozygote) and a recessive allele (not expressed in the heterozygote).

• This all-or-nothing expression is now called “complete” dominance

• Another form is “incomplete” dominance, where the phenotype of the heterozygote is intermediate between the two parental homozygotes. The classic case is red flowers x white flowers giving pink heterozygotes.

• How incomplete dominance works: each red flower color allele makes red pigment. The white alleles don’t make pigment. So, the red homozygotes make twice as much pigment as the heterozygotes. We perceive the difference in the amount of pigment as red vs. pink.

Co-dominance• In co-dominance, the heterozygote expresses both

parental types. A good example is the ABO blood group.

• There are 4 blood types: A, B, AB, and O. Red blood cells of type A have a glycolipid (a carbohydrate attached to a lipid in the membrane) on their cell membranes. B cells have a different glycolipid. AB cells have both glycolipids, and O cells have neither.

• The glycolipids are made by genes with the symbol I. The IA allele makes A glycolipids, and the IB allele makes the B glycolipids. People with AB blood have a heterozygous genotype: IA IB. They express both types of glycolipids on their red blood cells. This is what “co-dominant” means.

• O blood comes from the third allele, called i because it is recessive. Homozygotes (ii) don’t make either A or B glycolipids. An IA i heterozygote had A blood, and a IB i heterozygote makes B blood.

• This is an example of multiple alleles (3 alleles in this case: IA, IB, and i). Most genes have more than 2 alleles.

Single Genes Can Have Multiple Effects

• Sickle cell anemia—caused by a change in hemoglobin gene. Gives rise to many symptoms: skull deformation, heart failure, joint and muscle pain, spleen enlargement. Also—resistance to malaria.

Lethal Genes• In another variation on dominance,

some alleles are lethal when homozygous—they kill the organism before birth.

• Two examples: achondroplastic dwarves and Manx cats.

• The heterozygote shows the unusual phenotype.

• When two heterozygotes mate, their sperm and eggs combine randomly, producing ¼ DD, ½ Dd, and ¼ dd zygotes. BUT: the DD zygotes all die. This leaves only the Dd (dwarf) and dd (normal) types, in a ratio of 2:1, or 2/3 dwarf and 1/3 normal.

• Thus, dwarves and Manx cats don’t breed true: they always produce 1/3 of the “wrong” type of offspring.

More on Lethal Genes

Environmental Effects• Most inherited traits are affected by

environmental conditions.• For instance, the hydrangea has white,

pink, and purple versions. There are only 2 alleles: white and pigmented. The pink and purple come from growing the plants in different acidity conditions.

• Some effects are more direct. Manx cats have no tails due to a mutant allele. But, cats can also have no tail because it has been cut off—an environmental condition.

• Genetic traits are also affected by ‘background” genetics—other genes present. Former Chicago Cubs relief pitcher Antonio Alfonseca has a condition called polydactyly, having extra fingers and toes. He has 6 on each hand and foot. More commonly people with this condition have just a single extra digit with no bone in it, but the range is quite large

Two Genes Affecting One Trait• Most traits are due to the

interaction of several genes.

• New phenotypes can arise from the interactions between genes. Also, unusual ratios of offspring.

Continuous Variation• Many traits don’t seem to fall into

discrete categories: height, for example. Tall parents usually have tall children. Short parents have short children, and tall x short often gives intermediate height. In all cases, wide variations occur.

• Simple interactions between several genes can give rise to continuous variation. Also: variations caused by environment, and our inability to distinguish fine distinctions lead us to see continuous variation where there actually are discrete classes.

Independent Assortment• Much of Mendel’s work involved pairs of

genes: how do they affect each other when forming the gametes and combining the gametes to form the next generation?

• Simple answer: in most cases pairs of genes act completely independently of each other. Each gamete gets 1 copy of each gene, chosen randomly.

• Two genes: • 1. seed shape. Dominant allele S is

smooth; recessive allele s is wrinkled.• 2. seed color. Dominant allele Y is

yellow; recessive allele y is green.• Heterozygous for both has genotype Ss Yy,

which is smooth and yellow. Gametes are formed by taking 1 copy of each gene randomly, giving ¼ SY, ¼ Sy, ¼ sY, and ¼ sy.

• These gametes can be put into a Punnett square to show the types of offspring that arise. Comes out to 9/16 smooth yellow, 3/16 smooth green, 3/16 wrinkled yellow, and 1/16 wrinkled green.

Linkage

• Most pairs of genes assort independently.

• However, if two genes are close together on the same chromosome, they are said to be linked, which means the genes don’t do into the gametes independently of each other.

• The closer two genes are, the more the parental combination of alleles stays together. This relationship can be used to make maps of genes on chromosomes.

Some Common Genetics Diseases

• Tay-Sachs disease is a neural degenerative disease caused by the lack of the enzyme hexose aminidase A, which normally breaks down certain membrane lipids in the lysosomes, especially in the nerve cells of the brain. Without the enzyme, these lipids accumulate in the cells, poisoning them. The child is apparently normal at birth, but starting between 6 months and two years, the child has seizures and a loss of all skills such as crawling, sitting and feeding. 100% lethal in early childhood. No cure or treatment known.

• Tay-Sachs is a recessive genetic disease: the victim must inherit a defective copy of the gene from both parents. The parents are heterozygotes (carriers) who have no symptoms. There is a 1 in 4 risk of another Tay-Sachs child in a family where one was born.

• There is a reliable blood test that can detect heterozygotes. High risk parents can take the test to determine their risk level. Tay-Sachs is especially prevalent among Ashkenazi (Eastern European ) Jews. In American Jewish population, about 1 person in 27 is a carrier. The French-Canadians from the St. Lawrence River area, and their cousins, the Louisiana Cajuns, also have a high risk of Tay-Sachs.

Sickle-cell Disease• Sickle-cell disease is caused by a defective

hemoglobin molecule in the blood. The defect puts a hydrophobic amino acids on the outer surface of the protein instead of a hydrophilic amino acid. This causes the hemoglobin molecules to crystallize into long rods when the oxygen level in the blood gets low. These hemoglobin rods distort the red blood cells so they clog up the blood-carrying capillaries. The result is muscle pain, anemia, heart enlargement, kidney and spleen damage, and various other problems. Various medical treatments are used to ease the symptoms.

• Sickle cell disease is recessive: homozygotes are quite sick. Heterozygotes are normal (sometimes called sickle cell trait), although they do have a higher rate of sudden death while exercising, due to sickling of the red blood cells under extreme conditions.

• Sickle cell disease is common in West Africa, areas around the Mediterranean Sea, and in India, where malaria is found. Being a heterozygote confers a strong resistance to malaria, which has helped maintain this mutation in the human population. Other hemoglobin defects, such as hemoglobin C and thalassemia, confer malaria resistance and are found in the same populations. The malaria parasites live inside the red blood cells. The rods of hemoglobin that form when the cells sickle puncture and kill the parasites.

• About 6% US African-Americans carry the HbS allele.

Malaria vs. Sickle Cell Disease

Cystic Fibrosis• Cystic fibrosis is primarily a disease of the

lungs. The thin mucus that normally lines the lungs is replaced by heavy, thick mucus that traps bacteria and leads to lung infections. Other symptoms include salty skin and pancreas problems. In the US today, people with cystic fibrosis have an average life span of 33 years.

• Cystic fibrosis is caused by a defective chloride ion channel, a protein that lets Cl- ions in and out of the cell. When chloride leaves the cell, sodium ions follow it, and water molecules follow the sodium. In cystic fibrosis, the chloride ions don’t get out of the mucus-secreting cells, so not enough water is secreted to properly tin the mucus.

• Treatment: attempts to remove the mucus through percussion on the back, mucus-thinning sprays, and antibiotics to treat infections.

• Found primarily in Northern European populations: about 4% of US European-American populations are heterozygotes (no symptoms). There are DNA-based tests for this, but not 100% reliable.

Phenylketonuria• Phenylketonuria (PKU) is a disorder of

the metabolism: the cells are unable to break down phenylalanine, which is an amino acid found in all proteins. The result is that phenylalanine levels in the blood build up to 30 times the normal level. This poisons the developing brain, leading to severe mental retardation.

• PKU is a recessive condition: the parents are usually heterozygotes who have no symptoms. About 5% of the US population (all ethnic groups) is heterozygous for PKU.

• There is a very simple blood test for PKU, which is given to all infants born in the US. The disease is easily treated by giving the children a low-phenylalanine diet until their brains mature. Infants in most states are also tested for several other easily detected and treated metabolic diseases.

Some Dominant Traits• Huntington’s Disease is a neural

degenerative disease that doesn’t appear until the victim is 40 years old or more. It starts with clumsiness and involuntary twitching, progresses through paranoia and psychosis, and ends in paralysis and death. The folk singer Woody Guthrie had this disease.

• Dominant genetic diseases appear in heterozygotes. Homozygotes are rare because heterozygotes only rarely find and mate with each other. Huntington’s shows complete dominance: the rare homozygotes have the same disease as the heterozygotes.

• There is a genetic test: if it is positive, you will get the disease. Most people don’t take the test.

Marfan Syndrome• Marfan syndrome is a disease of the

connective tissue: the skeleton and cardiovascular system in particular. Symptoms include curvature of the spine, long fingers, tall stature, dislocated eye lens, and weakness of the aorta. People with Marfan’s sometimes die suddenly due to the rupture of their aorta. Abraham Lincoln might have had this disease. Also Osama bin-Laden.

• The disease is caused by an abnormal fibrillin gene. Fibrillin is one of the proteins that makes tissues elastic.

• Marfan’s is a dominant trait, meaning that the heterozygotes have the disease. People homozygous for Marfan’s show a more extreme version and don’t live past infancy. Just as in Huntington Disease, people with Marfan’s have a 50% chance of passing the disease to their offspring.

Retinoblastoma• Retinoblastoma is a hereditary form of

cancer. Like most hereditary cancers, it strikes young children, almost all before age 5. Tumors grow in the eyes, from the retinal precursor cells, the retinoblasts. It is quite treatable if caught early, using cryotherapy to freeze the tumors, or radiation and chemotherapy if necessary.

• About 40% of the cases are hereditary, inherited from a parent who had the disease. The other 60% are spontaneous: due to newly arising mutations. The hereditary cases usually affect both eyes, while the spontaneous cases are confined to one eye. It is inherited as a dominant trait, so 50% of an affected person’s children will get the disease. Homozygotes die as early embryos and are never born alive.

Schizophrenia: a Complex Genetic Trait

• A mental disease: thought disorders (inability to think logically), delusions (person is being spied on or persecuted, thoughts are being overheard by others), hallucinations (voices inside the head). Also lack of emotional engagement, odd walking gait, social withdrawal.

• NOT multiple personalities of “split” personality.

• Onset at any time, but generally age 16-25. Males and females equally affected.

• Treatable with anti-psychotic drugs. But: the person must keep taking the drugs even after feeling better.

More Schizophrenia• Degree of risk for schizophrenia is strongly affected by relatives who have the

disease:• 1% risk for the general population• 13% risk if you have 1 schizophrenic parent• 35% risk if you have 2 schizophrenic parents• Monozygotic (identical) twins: 50% risk• 13% of adopted children with a schizophrenic biological parent and normal

adoptive parents develop the disease.• This “runs in the family” phenomenon strongly implies genetic factors are involved.• Other factors are also involved: brain damage, viruses, family environment, life

experiences, diet, plus others. Any or all of these. • Mapping: large family studies examine markers on the chromosomes to find locations

associated with schizophrenia. That is, chromosomal locations where the alleles in a schizophrenic parent are also found in the schizophrenic child. Potential genes on chromosomes 22, 13, and 8.

• But: the genes have been difficult to confirm. They seem to affect some families but not others. Maybe multiple causes of the disease?