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Chapter : Genetics The Classic Approach
Mendel working in his garden Pea Plants!
Gregor Mendel Gregor Mendel combined his farmer’s skills with his training in mathematics. Mendel’s law of segregation states that each individual has two factors (called genes today) for each trait. Alternative forms of a gene having the same position on a pair of homologous chromosomes and affecting the same trait are now referred to as alleles.
Today we know that alleles occur at the same loci (position) on a chromosome. The factors segregate during the formation of the gametes and each gamete has only one factor from each pair. Fertilization gives each new individual two factors again.
Gene locus (locus = location)
The Inheritance of a Single Trait A capital letter indicates a dominant allele, which is expressed when present. An example is W for widow’s peak. A lowercase letter indicates a recessive allele, which is only expressed in the absence of a dominant allele. An example is w for continuous hairline.
Genotype and Phenotype Genotype refers to the genes of an individual which can be represented by two letters or by a short descriptive phrase. Homozygous means that both alleles are the same; for example, WW stands for homozygous dominant and ww stands for homozygous recessive. Phenotype refers to the physical appearance of the genotype!
Gamete Formation (sperm and eggs) Because homologous pairs separate during meiosis, a gamete has only one allele from each pair of alleles. If the allelic pair is Ww, a gamete would contain either a W or a w, but not both. Ww represents the genotype of an individual. Gametes are represented by W or w.
One-Trait Crosses (let’s breed!) In one-trait crosses, only one trait such as type of hairline is being considered. When performing crosses, the original parents are called the parental generation, or the P generation. All of their children are the filial generation, or F generation. Children are monohydrids when they are heterozygous for one pair of alleles.
If you know the genotype of the parents, it is possible to determine the gametes and use a Punnett square to determine the phenotypic ratio among the offspring. When a monohybrid reproduces with a monohybrid, the results are 3 : 1. This ratio is used to state the chances of a particular phenotype. A 3 : 1 ratio means that there is a 75% chance of the dominant phenotype and a 25% chance of the recessive phenotype.
One-Trait Crosses and Probability Laws of probability alone can be used to determine results of a cross. The laws are: (1) the probability that two or more independent events will occur together is the product of their chances occurring separately, and (2) the chance that an event that can occur in two or more independent ways is the sum of the individual chances.
In the cross of Ww x Ww, what is the chance of obtaining either a W or a w from a parent? Chance of W = ½, or chance of w = ½ The probability of these genotypes is: The chance of WW = ½ x ½ = ¼ The chance of Ww = ½ x ½ = ¼ The chance of wW = ½ x ½ = ¼ The chance of ww = ½ x ½ = ¼ The chance of widow’s peak (WW, Ww, wW) is ¼ + ¼ + ¼ = ¾ or 75%.
The One-Trait Testcross It is not always possible to discern a homozygous dominant from a heterozygous individual by inspection of phenotype. A testcross crosses the dominant phenotype with the recessive phenotype. If a homozygous recessive phenotype is among the offspring, the parent must be heterozygous.
The Inheritance of Many Traits Independent Assortment The law of independent assortment states that each pair of alleles segregates independently of the other pairs and all possible combinations of alleles can occur in the gametes. This law is dependent on the random arrangement of homologous pairs at metaphase.
Segregation and independent assortment
Two-Trait Crosses In two-trait crosses, genotypes of the parents require four letters because there is an allelic pair for each trait. Gametes will contain one letter of each kind in every possible combination. When a dihybrid reproduces with a dihybrid the results are 9 : 3 : 3 : 1.
Two-Trait Crosses and Probability It is possible to use the two laws of probability to arrive at a phenotypic ratio for a two-trait cross without using a Punnett square. The results for two separate monohybrid crosses are as follows: Probability of widow’s peak = ¾ Probability of short fingers = ¾ Probability of straight hairline = ¼ Probability of long fingers = ¼
The probabilities for the dihybrid cross: Probability of widow’s peak and short fingers = ¾ x ¾ = 9/16 Probability of widow’s peak and long fingers = ¾ x ¼ = 3/16 Probability of straight hairline and short fingers = ¼ x ¾ = 3/16 Probability of straight hairline and long fingers = ¼ x ¼ = 1/16
The Two-Trait Testcross A testcross is done when it is not known whether a dihybrid individual is homozygous dominant or heterozygous for both or one of the traits under consideration. A cross of a person heterozygous for both traits with a homozygous recessive person produces a 1 : 1 : 1 : 1 ratio.
Pedigree charts represent males as squares and females as circles. Recessive and dominant alleles have different patterns of inheritance. Genetic counselors construct pedigree charts to determine the mode of inheritance of a condition.
Autosomal recessive pedigree chart
Autosomal dominant pedigree chart
Autosomal Recessive Disorders Tay-Sachs Disease Tay-Sachs disease is common among United States Jews of central and eastern European descent. An affected infant develops neurological impairments and dies by the age of three or four. Tay-Sachs results from a lack of hexosaminidase A and the storage of its substrate in lysosomes.
Cystic Fibrosis Cystic fibrosis is the most common lethal genetic disorder among Caucasians. A chloride ion transport protein is defective in affected individuals. Normally when chloride ion passes through a membrane, water follows. In cystic fibrosis patients, a reduction in water results in a thick mucus which accumulates in bronchial passageways and pancreatic ducts.
Cystic fibrosis therapy
Phenylketonuria (PKU) Individuals with phenylketonuria lack an enzyme needed for the normal metabolism of phenylalanine, coded by an allele on chromosome 12. Newborns are regularly tested for elevated phenylalanine in the urine. If the infant is not put on a phenylalanine- restrictive diet in infancy until age seven when the brain is fully developed, brain damage and severe mental retardation result.
Autosomal Dominant Disorders Neurofibromatosis Small benign tumors, made up largely of nerve cells, occur under skin or on various organs. The effects can range from mild to severe, and some neurological impairment is possible; this disorder is variably expressive. The gene for this trait is on chromosome 17.
Huntington Disease Individuals with Huntington disease experience progressive degeneration of the nervous system and no treatment is presently known. Most patients appear normal until middle age. The gene coding for the protein huntingtin contains many more repeats of glutamines than normal.
Skin Color The inheritance of skin color, determined by an unknown number of gene pairs, is a classic example of polygenic inheritance. A range of phenotypes exist and several possible phenotypes fall between the two extremes of very dark and very light. The distribution of these phenotypes follows a bell-shaped curve.
Polygenic Disorders Many human traits, like allergies, schizophrenia, hypertension, diabetes, cancers, and cleft lip, appear to be due to the combined action of many genes plus environmental influences. Many behaviors, such as phobias, are also likely due to the combination of genes and the effects of the environment.
Multiple Allelic Traits Inheritance by multiple alleles occurs when more than two alternative alleles exist for a particular gene locus. A person’s blood type is an example of a trait determined by multiple alleles. Each individual inherits only two alleles for these genes.
ABO Blood Types A person can have an allele for an A antigen (blood type A) or a B antigen (blood type B), both A and B antigens (blood type AB), or no antigen (blood type O) on the red blood cells. Human blood types can be type A (I A I A or I A i), type B (I B I B or I B i), type AB (I A I B ), or type 0 (ii).
Inheritance of blood type
Incompletely Dominant Traits Codominance means that both alleles are equally expressed in a heterozygote. Incomplete dominance is exhibited when the heterozygote shows not the dominant trait but an intermediate phenotype, representing a blending of traits. Such a cross would produce a phenotypic ratio of 1 : 2 : 1.
Sickle-Cell Disease Sickle-cell disease is an example of a human disorder controlled by incompletely dominant alleles. Sickle cell disease involves irregular, sickle shaped red blood cells caused by abnormal hemoglobin. Hb A represents normal hemoglobin; and Hb S represents the sickled condition.
Hb A Hb A individuals are normal; Hb S Hb S individuals have sickle-cell disease and Hb A Hb S individuals have the intermediate condition called sickle-cell trait. Heterozygotes have an advantage in malaria-infested Africa because the pathogen for malaria cannot exist in their blood cells. This evolutionary selection accounts for the prevalence of the allele among African Americans.
Many genetic disorders and other traits are inherited according to laws first established by Gregor Mendel. Inheritance is often more complex, providing exceptions to Mendel’s laws but helping to explain an even wider variety in patterns of gene inheritance.
Chapter 24 : Chromosomes!
Amniocentesis Amniocentesis uses a needle to extract amniotic fluid from the uterus of a pregnant woman from the 14 th to 17 th week of pregnancy. Up to 400 chromosome and biochemical problems can be detected by culturing fetal cells that are in the amniotic fluid. There is a slight risk of spontaneous abortion with this procedure.
Chorionic Villi Sampling Chorionic villi sampling (CVS) uses a thin suction tube to sample chorionic cells from the placenta as early as the fifth week of pregnancy. The cells do not have to be cultured, and karyotyping can be done immediately. CVS carries a slightly greater risk of spontaneous abortion but can be performed earlier than amniocentesis.
Chorionic villi sampling
Karyotyping Sampled fetal cells are stimulated to divide in culture medium and another chemical stops division during metaphase when chromosomes are highly condensed. The stained cells are photographed and can be paired based on stained cross- bands, and size and shape.
Human karyotype preparation
Normal male karyotype
Down syndrome karyotype
Nondisjunction in meiosis I
Nondisjunction in meiosis II
Normal development depends on the presence of two of each kind of chromosome, but an extra chromosome is tolerated more than a missing chromosome. The Barr body is an inactive X chromosome and is seen whenever more than one X chromosome is present (i.e., XX, XXY, XXX). Cells of females function with a single chromosome just as those of males do.
Down Syndrome Down syndrome is caused by trisomy 21, three copies of chromosome 21 as a result of nondisjunction. Symptoms include mental retardation, short stature, eyelid fold, flatter face, a palm creases, and stubby fingers, among others. Nondisjunction usually occurred in producing the mother’s egg and risk increases at age 40.
Abnormal autosomal chromosome number
The genes causing Down syndrome are located on the bottom third of chromosome 21. In particular, the Gart gene leads to a high level of purines, which contribute to mental impairment but may allow future preventive treatment.
Changes in Sex Chromosome Number The presence of a Y chromosome determines maleness. The SRY gene on the short arm of the Y produces a testis-determining factor that begins the development of a male; otherwise an embryo develops as a female. An abnormal number of sex chromosomes is the result of inheriting to many or too few X or Y chromosomes.
Turner Syndrome Individuals with Turner syndrome are females that have only one X chromosome; therefore they are XO. They are short, with a broad chest, and webbed neck. They do not undergo puberty or menstruate, and there is a lack of breast development. Intelligence is normal and individuals can lead normal lives.
Klinefelter Syndrome Individuals with Klinefelter syndrome are males that have two or more X chromosomes in addition to a Y chromosome. The Y chromosome drives development as a male but gonads are underdeveloped and breasts develop. Klinefelter males are usually slow to learn but are not mentally retarded.
Abnormal sex chromosome number
Poly-X Females A poly-X female has more than two X chromosomes and extra Barr bodies in the nucleus. An XXX female has a normal phenotype except there may be menstrual difficulties, but she is fertile; her children usually have normal karyotypes. Females with XXXX are usually tall and severely retarded; they may menstruate normally.
Jacobs Syndrome Jacobs syndrome males are XYY which can only result from nondisjuction during spermatogenesis. They tend to be tall, have persistent acne, and have speech and reading problems. At one time it was suggested that XYY males were unusually aggressive, but this was found not to be true.
Deletions and Duplications Deletions occur when a single break causes a lost end piece, or two breaks result in a loss in the interior. An individual who inherits a normal chromosome from one parent and a chromosome with a deletion from the other parent no longer has a pair of alleles for each trait, and a syndrome can result.
In Williams syndrome, chromosome 7 loses an end piece and children have a pixie look and the skin ages prematurely from lack of the gene that governs elastin production. An end piece of chromosome 5 produces cri du chat syndrome where larynx is abnormal and the infant’s cry is like that of a cat, the head is small, and there are facial abnormalities.
Duplication results in a chromosome segment being repeated in the same chromosome or in a nonhomologous chromosome, producing extra alleles for a trait. An inverted duplication in chromosome 15 causes inv dup 15 syndrome with poor muscle tone, mental retardation, and related symptoms.
Translocation Translocation is exchange of chromosomal segments between two, nonhomologous chromosomes. In a small percent of cases, a translocation between chromosomes 21 and 14 causes Down syndrome. The tendency for this particular translocation can run in the family of either the mother or father of affected individuals.
Alagille syndrome results from a deletion of chromosome 20 or a translocation that disrupts an allele on chromosome 20. The symptoms for Alagille syndrome range from mild to severe, so people may not be aware they have the syndrome.
Inversion Inversion involves a segment of a chromosome being turned 180 degrees; the reverse sequence of alleles can alter gene activity. Crossing-over between inverted and normal chromosomes can cause recombinant chromosomes due to the inverted chromosome needing to form a loop to align.
X-Linked Alleles The key for an X-linked problem shows the allele attached to the X as in: X B = normal vision X b = color blindness. Females with the genotype X B X b are carriers because they appear to be normal but each son has a 50% chance of being color blind depending on which allele the son receives. X b X b and X b Y are both colorblind.
Cross involving an X-linked allele
X-Linked Disorders In pedigree charts that show the inheritance pattern for X-linked recessive disorders, more males than females have the trait because recessive alleles on the X chromosome are expressed in males. A grandfather passes an X-linked recessive disorder to a grandson through a carrier daughter. X-linked recessive disorders include red- green color blindness, muscular dystrophy, and hemophilia.
X-linked recessive pedigree chart
Color Blindness Three types of cones are in the retina detecting red, green, or blue. Genes for blue cones are autosomal; those for red and green cones are on the X chromosome. Males are much more likely to have red- green color blindness than females. About 8% of Caucasian men have red- green color blindness.
Muscular Dystrophy Muscular dystrophy is characterized by the wasting of muscles. The most common form is Duchenne muscular dystrophy; this is an X-linked disorder, occurring in 1 of 3,600 males. Muscles weaken, frequent falls and difficulty in rising occur early; death occurs by age 20.
Duchenne muscular dystrophy involves the absence of a protein called dystrophin that is involved in the release of calcium from the sarcoplasmic reticulum of muscle cells. The lack of dystrophin causes calcium to leak into the cell, which promotes the action of an enzyme that dissolves muscle fibers. A test is now available to determine the carriers of Duchenne muscular dystrophy.
Hemophilia Hemophilia refers to the lack of one of several clotting factors that leads to excessive bleeding in affected individuals. Hemophiliacs bleed externally after injury, but also bleed internally around joints. Hemorrhages can be stopped with blood transfusions or a biotechnology clotting factor.
Fragile X Syndrome Fragile X syndrome is an X-linked genetic disorder with an unusual pattern of inheritance. Individuals with this syndrome (one in 1,500 males and one in 2,500 females) have a base triplet repeat (CGG) in a gene on the X chromosome. Children may be autistic or hyperactive with speech difficulties.
Adults have large testes if male, and big protruding ears. They are short in stature and the face is long with a prominent jaw. A person with a smaller number of CGG repeats and minor or no symptoms is said to have a premutation and can pass it to their children where the number increases and the condition is severe.
The frequency of recombinant gametes that occurs due to the process of crossing- over has been used to map chromosomes. Crossing-over data is used to map the chromosomes of animals, such as fruit flies, but is limited in mapping human chromosomes because we do not control the crosses.
Cross involving linked genes
Abnormalities arise when humans inherit an incorrect number of sex chromosomes. Traits unrelated to the gender of an individual are controlled by genes located on the sex chromosomes. Males express X-linked recessive disorders because they inherit only one X chromosome. Genes that occur on the same chromosome form a linkage group and tend to be inherited together.