Genetic Control of Growth & Maturation

Gregor Mendel (1822-1884) Mendel studied the inherited traits of pea plants.

Gregor Mendel (1822-1884) From his observations Mendel deduced that: Each characteristic must be determined by a hereditary factor There is a pair of hereditary factors; one from each parent

Gregor Mendel (1822-1884) The law of uniformity: When two homozygotes with different alleles are crossed, all the offspring are identical and heterozygous. The law of segregation: Each individual possesses two genes for a particular characteristic, only one of which can be transmitted. The law of independent assortment: Members of different gene pairs segregate to offspring independently of one another.

Mendel’s Observations Generation 1: Yellow Round x Green Wrinkled All Yellow Round offspring Generation 2: Yellow Round x Yellow Round Generation 3: Yellow Round, Yellow Wrinkled, Green Round. Green Wrinkled

Explanation of Mendel’s Observations Generation 1: Yellow Round (YYRR) x (Green Wrinkled (yyrr) Generation 2: Yellow Round (YyRr) x Yellow Round (YyRr) Generation 3: 9 Yellow Round (YYRR or YyRr) 3 Yellow wrinkled (Yyrr or Yyrr) 3 Green Round (yyRR or yyRr) 1 Green Wrinkled (yyrr)

Pea Experiment Click on the link below when you are connected to the internet Pea Soup Website

Gene

Alleles The two copies of each gene are called alleles, which may be identical (AA and aa) or different (Aa).

Homozygous Refers to the state of carrying identical alleles at one or more gene loci (e.g. AABB or aabb).

Heterozygous Refers to the state of carrying different alleles at one or more gene loci (e.g. AaBb).

Segregation of Alleles Law of segregation is that alleles segregate, or separate, when the F1 generation produces gametes. Alleles reside at specific loci, or sites, on the chromosomes within the DNA molecule. A pair of homologous chromosomes contains two alleles at each locus and during gamete formation of meiosis, each gamete receives only one member of each homologous pair of chromosomes. Therefore, each gamete also receives only one allele of a particular locus.

Cytogenetics The study of Chromosomes 1903 Sutton and Boveri independently proposed that the vehicle of hereditary factors or genes were the thread-like structures seen by light microscopy in the nucleus of each cell. Chromosomes because of their affinity to take up certain stains (Greek: chroma, colour; soma, body). Chromosomes are only being seen during the metaphase stage of cell division when they are maximally contracted. Plant Chromosomes: von Nägeli in 1842. Animal Chromosomes: Flemming (mitosis) 1882.

Karyotype Chromosome Complement of the Cell (1956) Karyotyping is the process of imaging the chromosomes of the cell 23 pairs of chromosomes 44 autosomes + 2 sex chromosomes 46, XX = Normal female 46, XY = Normal male

Genotype The genetic make up of the individual. Typically, one refers to an individual's genotype with regard to a particular gene of interest It refers to what combination of alleles the individual carries (either homozygous or heterozygous).

Phenotype Any feature or characteristic of an organism or any group of characteristics (e.g. metabolism, physiology, or morphology). The phenotype is the result of the interaction of the gene and environmental components.

Human Genome Project The Human Genome Project (HGP) aimed to map and understand of all the genes of human beings. In 1911, Alfred Sturtevant, then an undergraduate researcher in the laboratory of Thomas Hunt Morgan, realized that he could - and had to, in order to manage his data - map the locations of the fruit fly (Drosophila melanogaster) genes whose mutations the Morgan laboratory was tracking over generations. Sturtevant produced the very first gene map.

Human Genome Project The hereditary material of all multi-cellular organisms is the famous double helix of deoxyribonucleic acid (DNA), which contains all of our genes. DNA, in turn, is made up of four chemical bases, pairs of which form the "rungs" of the twisted, ladder-shaped DNA molecules. All genes are made up of stretches of these four bases, arranged in different ways and in different lengths.

Human Genome Project By February 2003 HGP researchers fully mapped the the human genome. determining the order, or "sequence," of all the bases in our genome's DNA; making maps that show the locations of genes for major sections of all our chromosomes; and producing what are called linkage maps, through which inherited traits (such as those for genetic disease) can be tracked over generations. The HGP has revealed that there are probably somewhere between 30,000 and 40,000 human genes 50,000 genes to as many as 140,000). National Human Genome Research Institute

Genetic Variation Program Most of any one person's DNA, about 99.5 percent, is exactly the same as any unrelated person's DNA. Differences in the sequence of DNA among individuals are called genetic variation. Genetic variation explains some of the differences among people, such as eye color and blood group. Genetic variation also plays a role in whether a person has a higher or lower risk for getting particular diseases. Single gene differences in individuals account for some traits and diseases, such as the ABO blood group, cystic fibrosis and sickle cell disease.

Genetic Variation Program More complex interrelationships among multiple genes and the environment are responsible for many common diseases, such as diabetes, cancer, stroke, Alzheimer's disease, Parkinson's disease, depression, alcoholism, heart disease, arthritis and asthma. The Genetic Variation program supports research on genetic variation and how it relates to diseases, responses to drugs and environmental factors.

Genetic Expression If all cells come from the one original zygote, how can the cells in the body vary so much Some genes are permanently switched on enzymes required for respiration etc Some genes become switched off because they are no longer required to be functional in that particular cell or tissue. Insulin is produced in pancreas cells, which must have the gene that codes for insulin switched on, and genes that are un-related to the role of the pancreas can be switched off. Some other genes that will be functional during specialisation determine the physical characteristics of the cell, i.e. long and smooth for a muscle cell or indented like a goblet cell

Height Polygenetic control

Parental Size Average height of siblings approximates average height of parents Parental stature adjusted growth curves Birth size poorly correlated with adult size Birth size correlated to mother’s size

Walton and Hammond (1938) Crossed large Shire horses with small Shetland ponies.

Walton and Hammond (1938) Offspring of the crosses delivered to Shire dams were heavier than that of pure Shetland ponies, but below that of pure Shire offspring. In contrast, the reciprocal cross-delivered to the Shetland dam was of the same weight at birth as the Shetland purebred foal. The Shetland mother was able to down regulate the in utero growth of her foal sired by the much larger Shire horse, while the in utero environment provided by the larger Shire mother facilitated enhanced growth.

Allen et al. 2004 Allen et al. (2004) Confirmed the original observations of Walton & Hammond (1938) that a genetically large foal cannot reach its normal birthweight when gestated in a uterus that is smaller than normal, and the runting effect persists throughout life. Furthermore, that genetically small foals will be born heavier than usual if gestated in the uteri of larger than normal mares and, similarly, this increased size persists to adulthood

14 months of age 3 years of age Tb-in-P vs Tb-in-Tb Tb-in-P vs Tb-in-Tb P-in-Tb vs P-in-P P-in-P vs P-in-Tb

Allen et al. 2004 Clear maternal size influence at birth Lasting effect in postnatal development Larger mother provided Larger placental area Greater microcotyledon density

Skin Colour Skin colour depends on the degree of melanin found in skin cells. There are two genes that control the production of melanin, each of which has a dominant and recessive expression. 16 combinations of genotype when coding for skin colour, as seen below.

Skin Colour # Genotype 1 M1M1M2M2 2 M1M1M2m2 3 M1M1m2m2 4 M1m1m2m2 5 m1m1m2m2 Phenotype Black Skin Dark Brown Skin Brown Skin Light Brown Skin White Skin A person is born with one of five colours. External factors such as the UltraViolet light from the sun modify the genetic expression of colour.

Sex Linked Inheritance A recessive trait on the X chromosome can find expression in a male

Sex Linked Inheritance Father’s contribution determines the sex of the child.

Hemophilia A Mainly exhibited in males, due to recessive gene on X chromosome. Only exhibited in double recessive females. Sons of hemophiliac males will not have the gene All daughters of male hemophiliacs will be carriers

Genetic Disorders Chromosomal Disorders Numerical (Aneuploidy) due to nondisjunction. Structural chromosomal due to a break in chromosome(s).

Genetic Disorders Chromosomal Disorders Numerical (Aneuploidy) due to nondisjunction 1st or 2nd division of meiosis. An extra copy of a chromosome (trisomy) or a missing copy of a chromosome (monosomy). Aneuploidy can also occur at mitosis after conception and leads to chromosomal mosaicism, a mixture of two or more cell lines each having a different number of chromosomes.

Genetic Disorders Mendelian Disorders Caused by a mutant allele or pair of mutant alleles at a single gene locus. Either inherited or due to a new mutation. Autosomal dominant or autosomal recessive. Homo vs Heterozygous, Male vs Female? Variable expressivity. Penetrance percentage of individuals exhibiting symptoms or signs E.g. reduced penetrance in neurofibromatosis, a disorder characterized by multiple brown skin patches and benign growths.

Genetic Disorders Mendelian Disorders Autosomal recessive disorders only manifest in the homozygote. Both sexes can be affected and heterozygotes (or carriers) are normal phenotypically. Most individuals affected by an autosomal recessive disorder are born to healthy carrier parents. 25% chance of homozygous normal 50% chance of unaffected heterozygote carriers 25% chance of having a homozygous affected offspring.. Cystic fibrosis is an autosomal recessive disorder progressive lung damage and poor growth

Genetic Disorders Mendelian Disorders Autosomal recessive disorders only manifest in the homozygote. Both sexes can be affected and heterozygotes (or carriers) are normal phenotypically. Most individuals affected by an autosomal recessive disorder are born to healthy carrier parents. 25% chance of homozygous normal 50% chance of unaffected heterozygote carriers 25% chance of having a homozygous affected offspring.. Cystic fibrosis is an autosomal recessive disorder progressive lung damage and poor growth

Genetic Disorders Mendelian Disorders Autosomal recessive disorders only manifest in the homozygote. Both sexes can be affected and heterozygotes (or carriers) are normal phenotypically. Most individuals affected by an autosomal recessive disorder are born to healthy carrier parents. 25% chance of homozygous normal 50% chance of unaffected heterozygote carriers 25% chance of having a homozygous affected offspring.. Cystic fibrosis is an autosomal recessive disorder progressive lung damage and poor growth

Genetic Disorders Multifactorial Disorders Multifactorial disorders occur in more than one member of the family but do not follow a mendelian pattern of inheritance. Interaction between environmental factors and a number of genes Cleft lip, palate, spina bifida and common disorders in adults (e.g. diabetes mellitus, cancer, schizophrenia) are thought to be multifactorial in origin. The risk for an individual of developing a multifactorial disorder is determined by the number of affected members in the family and the relationship to the patient.

Chromosome Aneuploidy Aneuploidy = wrong number Sex Chromosome Aneuploidies Wrong complement of sex chromosomes E.g. 47,XXX; 45,X0 Autosomal Aneuploidies Trisomy 21: Down Syndrome

47, XXX 1 : 960 Normal in appearance Usually fertile 15-25% are mildly mentally retarded Occurs due to nondisjunction in meiotic division of female

Turner’s Syndrome 1 : 2,500 live female births (1:5,000 total live births). There are indications that as few as 1:50 45, X0 conceptions are born alive. The others spontaneously abort. This suggests that the monosomy tends to be lethal.

Turner’s Syndrome "Webbing" of the neck is often seen at birth and beyond. The skin between the mastoid region and the shoulder expands before birth to cover a swollen jugular lymph sac. The swelling usually goes down before birth, but the excess skin persists as a redundant fold. A broad, shield-shaped chest and widely spaced nipples are also typical in this syndrome. Short for their age; as adults they rarely exceed 5 feet in height.

Turner’s Syndrome Ovarian dysgenesis and are infertile. Cardiovascular abnormalities. Many have a low posterior hairline. Behind siblings in intellectual development. Poor sexual development internally and externally.

45, Y0 Given that 45, X0 individuals exist, one might expect the viability of its male counterpart, 45, Y0. However, no such adults, children or embryos have been reported. Indeed, Y0 or YY cells have never been observed. It has been suggested that these theoretically possible chromosome constitutions are incompatible with life, even with life as a very early embryo. Apparently there are genes necessary for life located on the X chromosome

Klinefelter Syndrome 47, XXY Incidence 1 : 1080

Klinefelter Syndrome 47, XXY Small testes, hyalinization of seminiferous tubules; aspermatogenesis Often tall with disproportionately long limbs. Intelligence is less than in normal siblings. About 40% of these males have gynecomastia

47,XYY “the criminal type” Adults with 47, XYY syndrome may exhibit a pockmarked face owing to severe acne during puberty. Growth is often accelerated during mid-childhood, so adults with this syndrome are often very tall. Severe acne may develop in puberty, leading to a pock-marked face in adult life. On the other hand, not all individuals are so affected by acne. Indeed, both physical abnormalities and behavioral aberrances may be absent.

47,XYY “the criminal type” Nevertheless, one study showed that among institutionalized male juvenile delinquents, one in 35 had a 47, XYY karyotype. This rate is 24 times the incidence of 47, XYY karyotype in all newborn males. On the basis of this, the association with behavioral problems is significant.

Down Syndrome Trisomy 21 Virtually all individuals with Down syndrome are mentally retarded, with the IQ most often in the 25 to 50 range. Congenital malformations of the heart are present in over half of these persons, and there is a 15-fold increase in risk for developing leukemia. Characteristic face and physique.

Down Syndrome - Trisomy 21 Maternal Age Incidence 20-24 1:1400 25-29 1:1100 30-34 1:700 35 1:350 37 1:225 39 1:140 41 1:85 43 1:50 45+ 1:25 Risk increases with maternal age

Mosaicism Two or more cell types containing different numbers of chromosomes. This example is for Down Syndrome but it can occur for all aneuploidies.

Trisomy 18 – Edwards Syndrome 47, XX, +18 or 47, XY, +18 1 : 3,300 live births. It is more severe than Down syndrome. Estimated that 95% of trisomy 18 fetuses abort spontaneously. Of those born alive, 30% die within a month of birth, 50% by two months and only 10% survive the first year of life. Failure to thrive, mental retardation. Half or more show growth deficiency and hypertonicity after the neonatal period. Over 130 abnormalities associated with trisomy 18 have been noted in the literature.

Trisomy 18 – Edwards Syndrome Clenched fist and over lapping fingers. Edward syndrome babies exhibit an unusual posture of the hands. The hands are clenched with the index finger overlapping the next and the 5th over the 4th Also common is "rocker bottom deformity" of the feet - prominent calcaneus bones and dorsiflexion, resulting in a convex plantar surface. Short sternum, narrow pelvis

Patau Syndrome - trisomy 13 47, XX, +13 or 47, XY, +13 1 : 5,000 live births, and the sex ratio is close to 1:1. Half of the infants with it die within a month of birth. Severe mental retardation and varying degrees of incomplete development of the brain are characteristic. Growth retardation, sloping forehead, eye and ear malformations.

Patau Syndrome - trisomy 13 Of the many abnormalities that can occur in this defect, the most consistent are cleft lip (60 to 80% of the cases), cardiac malformations (80%), and the brain defects coupled with severe mental retardation. Almost all organ systems may show defects.

Patau Syndrome - trisomy 13 Because of the high mortality (only 18% survive the first year), coupled with severe organ defects including the brain, at least some pediatricians believe that no medical means should be employed to prolong the life of these individuals

Cri-du-chat Syndrome In 1963, French geneticist Jerome Lejeune first described the syndrome noting the mewing, cat-like cry in affected newborns. He was a pro-life pediatrician who discovered many connections between chromosome abnormalities and diseases. He devoted a major part of his career treating children affected by Down’s syndrome.

Cri-du-chat Syndrome 46, XX, 5p- or 46, XY, 5p- 5p- indicates deletion of the short arm of chromosome number 5. Deletion of the long arm would be abbreviated 5q-, q indicating the long arm of this chromosome. Also present in 100% of the cases are microcephaly, mental retardation and slow growth. Almost all exhibit optic hypertelorism (widely spaced eyes), and 85% exhibit epicanthic folds.

Cri-du-chat Syndrome Also present in 100% of the cases are microcephaly, mental retardation and slow growth. Almost all exhibit optic hypertelorism (widely spaced eyes), and 85% exhibit epicanthic folds. Common symptoms are webbing of the fingers and toes, abnormal motor skill development, and a single line in the palm of the hand, known as a Simian crease. This is a rare condition, occurring about once in every 50,000 live births.