Introductory Genetics Lecture Notes

INTRODUCTORY GENETICS LECTURE Species – populations that can and do reproduce and have fecund/fertile offspring Populations Made up of individuals Made up of organs Made up of tissues Made up of cells – most of which have a nucleus and cytoplasm Inside most cells is a cell nucleus, like a little walled city. Inside the nucleus are the chromosomes, the “colored bodies” that carry most of the genetic information for determining what sort of a living organism you become, your nuclear DNA. Inside the cell, but out in the cytoplasm, outside the nucleus, are the mitochondria – the energy factories of the cells. The mitochondria also carry some of your genetic information, inherited only from your mother, your mtDNA. The chromosomes inside the nucleus are physical structures, and consist of long strands of a specific type of nucleic acid, deoxy-ribo-nucleic acid or DNA sequences in the form of a double helix (like a spiral staircase, but twisted), around a protein core. The sides of the ladder or helix provide stability, and the rungs connecting the sides are made up of pairs of bases, bonded in the middle. There are four main bases, A (adenine), C (cytosine), T (thymine), and G (guanine). A always bonds with T and C always bond with G. The bases are like letters. Each set of three adjacent bases forms a word or “codon” that specifies for one of 20 amino acids to be written into the protein sentence when building proteins. 2 DNA = deoxy-ribo-nucleic acid. DNA likes to do two things: ● Likes to reproduce itself through either meiosis or mitosis (more later) ● Likes to allow RNA to “read” its instructions and then go out into the cytoplasm and make proteins Chromosomes carry most of your genetic code or genome (the sum total of all your genetic information). Think of this genetic information as: (1) the directions or blueprints, for the production/synthesis of proteins from amino acids, which results in building the structure of the particular kind of organism you are, your anatomy at all levels; it is also (2) the instruction manual for running the organism – your physiological processes, how things work, grow, and are maintained, especially through proteins known as enzymes that are responsible for the cell’s chemical reactions; it is also (3) the repair manual for fixing the organism – for repairing damage due to injury or aging, for fighting off infections, and for coping with all sorts of environmental stresses like radiation and toxins Each and every cell in your body that has a nucleus has ALL of the genetic material encoded on the chromosomes. However, most of the genetic information in each cell is INACTIVE. There is a very complicated system for determining which genes are functioning or “turned on” or active, and the rates at which they are transcribed into proteins, in each cell type. Thus, your liver cells only express the genes related to liver structure/function/repair, even though they carry all the genes. Your skin cells only express the genes related to skin cell structure/function/repair, even though they carry all the genes. Scientists are just now beginning to understand the mechanisms by which cells become differentiated (permanently turn off most of the genes in the nucleus), and the mechanisms by which the remaining “on” genes are regulated – which ones are transcribed, when, under what conditions, and at what rates. This is the emerging field of “epigenetics” about which more later. For now, let’s just stick to the chromosomes and the genes they carry. Characteristic number of nuclear chromosomes for each “normal/typical” member of a species (the same type of organism); chromosomes like to travel in pairs. For typical humans, there are 46 chromosomes; thus, 23 pairs. However, you can have 45 chromosomes, or 47 or 48, and still be human. You can also be missing pieces of a chromosome, or have extra pieces of a chromosome. Chromosomes consist of many “genes,” interspersed with other DNA that may not produce proteins, but which contains instructions or switches for controlling the protein-producing genes. Of the 46 chromosomes in typical humans, they are numbered, from the largest pair, #1, to the smallest pair, #22. (Actually, pair #21 is smaller than pair #22, but a mistake was made in the original determination of size and numbering, and it’s been left that way). #21 is actually the smallest. The first 22 pairs are called “autosomes.” They are homologous, which means that the two members of the pair have the same genes at the same locations along the chromosomes. They have matching genes. #1 goes with #1, #2 goes with #2, #3 goes with #3, etc. etc. The 23rd pair of chromosomes are not autosomes. They are the sex chromosomes. They come in two different sizes and types, X and Y. The X chromosome is a large chromosome with many genes, while the Y chromosome is a little teeny tiny chromosome with only a few genes, which are mostly different from the ones on the X chromosome. If the 23rd pair of chromosomes are XX then (usually) you are a FEMALE, and your 23rd pair of chromosomes, the sex chromosomes, are homologous, just like your 22 pairs of autosomes. If the 23rd pair of chromosomes are XY then (usually) you are a MALE, and your 23rd pair of chromosomes is not a homologous pair. They are a heterologous pair (“different loci”), with different genes on each member of the pair. Thus, males have only one copy of the genes on the X chromosome, and one copy of the genes on the Y chromosome. Typically/normally, each human being inherits exactly 50% of their chromosomal genetic material from their mother, and exactly 50% of their chromosomal genetic material from their father. We’ll talk about how that happens shortly. For now, just know that one chromosome of each pair comes from your mother, and one pair from your father. #1 from mother #2 from mother #3 from mother #1 from father #2 from father #3 from father And so on . . . #23 – everyone gets an X from their mother (either her mother’s X, or her father’s X) #23 – if you get an X from your father as well, which is his mother’s X, you are a FEMALE (XX) #23 – if you get a Y from your father, which is his father’s Y, you are a MALE (XY) Y chromosomes can only be inherited from your father, obviously. Each male has ONE of his mother’s X chromosomes, plus his father’s Y. Each female has ONE of her mother’s X chromosomes, plus her father’s X. Genes on the X and Y chromosomes are mostly different, so males have only one copy of most genes on the X and one copy of each gene on the Y, while females have two copies of the genes on the X, and none of the genes on the Y. Defining what a gene is, exactly: ● Gene: A DNA sequence that codes for a functional polypeptide or RNA product ● Simple notion of a gene: A segment of a chromosome that carries the information for one particular protein or trait ● Functional definition of a gene: That portion of the DNA molecule (or that section of the chromosome) that carries the codon sequence for a particular protein Locus/loci/logous: the physical location(s) of a gene on a chromosome, like the street address. Allele: The alternative/variant forms of a gene or DNA sequence that may be found at a given locus. Some loci have only one allele, some have two, and some have many alternative forms. Alleles come in pairs, one on each chromosome of the pair of chromosomes. Example: The gene for one blood type system, the ABO system, has three alleles, A, B, and O. The gene for a different blood type system, the MN system, has two alleles, M and N. Two kinds of cells Somatic cells – “cells of the body” with 46 chromosomes in each cell nucleus for typical humans Sex cells – also known as “gametes” – the ones that will contribute to making the next generation: Sperm in males, eggs (ova) in females. Each sex cell, or gamete, should have 23 chromosomes, 1 member of each homologous pair of autosomes, #1-22, plus one sex chromosome, either X or Y. All eggs carry an X chromosome, sperm can be either X-bearing (daughter) or Y-bearing (son). When the egg and the sperm meet at fertilization, they join together to restore the total complement of 46 chromosomes typical of our species. The single-cell fertilized egg is known as a zygote. Dominant and recessive alleles ● Dominant alleles express themselves/are detectable/show up whether they are paired with another identical copy, or with a different allele. ● Recessive alleles express themselves/are detectable/show up ONLY when they are paired with another identical copy of the same recessive allele. Dominance vs. recessiveness has nothing to do with GOOD vs. BAD, or COMMON vs. RARE. Co-dominance – when you have two different alleles, but both are dominant alleles, so they both show up. Incomplete penetrance – the specific allele for a trait is present, but isn’t always expressed. It probably depends on subtle differences in the environment during gestation, most likely through epigenetic processes. Influence of other genes – sometimes the identical genes in two different people can be expressed differently depending on the other genes each person inherited to go along with that one. Influence in terms of which parent donated the chromosome (and therefore the gene) – also known as “parental imprinting” – examples include Huntington’s disease and Prader-Willi/Angelmann’s syndromes. Again, perhaps through the mechanisms of epigenetics. Homozygous and heterozygous conditions: “homo” from the Greek meaning SAME, “hetero” from the Greek meaning DIFFERENT. “Zygous – in the zygote.” Effects of a particular gene, whether good or bad, are dependent not only on whether it is paired with its identical allele (homozygous) or a different allele (heterozygous), but also on the environment. An allele can be good in some circumstances/environments, and bad in others. Reproduction of cells - for growth (mitosis) and for production of gametes (meiosis) Mitosis: makes 2 identical cells out of the original cell; these are referred to as “daughter cells” ❖ the 46 chromosomes duplicate themselves (double stranded DNA) – originals + copies ❖ they line up individually as doubled chromosomes along the equator of the cell (not in their homologous pairs, just randomly) ❖ the cell divides, separating the double strands – original + copy are pulled apart ❖ the cytoplasm also splits equally and the cell divides into two ❖ result is two "daughter" cells with 46 chromosomes, each identical to parent cell (if no mistakes have been made) Meiosis: two-stage process, makes 4 cells are not identical to original cell ❖ the 46 chromosomes duplicate themselves – originals + copies ❖ they line up in homologous pairs of double-stranded chromosomes along the equator of the cell; they pay no attention to the way the other homologous pairs are lined up ❖ the 1st division separates the two members of the homologous pairs of double-stranded chromosomes; they go to different ends of the cell, and it divides into two ❖ result is two “daughter” cells, each with 23 chromosomes in a double-stranded condition (#1, #2, #3, #4, etc.) ❖ the 2nd division is just like mitosis, in each of the daughter cells from the 1st division, the 2nd division separates the double strands of each chromosome ❖ the cell divides, separating the double strands – original + copy are pulled apart ❖ the cytoplasm also splits and the cell divides into two ❖ result is a total of four “daughter” cells with 23 single-stranded chromosomes, one member of each pair, each in a single state – in reality you get 4 sperm, but only one egg out of this process, because all of the cytoplasm goes into one daughter cell at each division, the rest become "polar bodies" and deteriorate. Sperm are basically just nuclei with tails – swimming nuclei – with very little cytoplasm. In males, sperm are made continuously in the testicles, inside the scrotum, from puberty through old age – they are most numerous when you are young, and decline in numbers and viability/zest as you get older. Every round of meiosis in the testicles produces 4 sperm from one precursor cell. In females, eggs are formed in the ovaries before the woman is born, when she is still in her mother’s uterus. They begin the process of meiosis, of making eggs, before the woman herself is even born; but they don’t complete the process then. For women between menarche (first menstrual cycle) and menopause (end of menstrual cycles), each month that she is neither pregnant nor nursing intensively, one egg-precursor cell finishes meiotic division and is released from the ovaries to travel down the Fallopian tubes looking for Mr. Right. A word about Mitochondrial DNA Mitochondria are the energy factories of the cells. They are located in the cytoplasm surrounding the nucleus. The egg carries all the cytoplasm of the precursor cell; the sperm carries only the nuclear DNA, no cytoplasm, therefore no mitochondria and no mtDNA. You therefore inherit your mitochondria and its DNA from your mother only. The mtDNA is passed intact from mothers to children; its genes are not shuffled and recombined each generation the way nuclear DNA is. Meiosis and fertilization, followed by mitosis: the great dance of life Meiosis produces sex cells (gametes), the sperm and egg, each carrying one member of each of the 22 homologous pairs and one sex chromosome. When fertilization occurs, the egg and sperm unit to form a zygote with 46 chromosomes. The single-celled zygote then divides by MITOSIS to form embryo-fetus-child-adult, etc. The non-gene DNA in the nuclear chromosomes directs the differentiation of the cells so that they know when and how to grow, how to function, etc. Modes of Inheritance Which parent determines the sex of the child? Father Which parent can pass on alleles on the Y chromosome? Father Which child can inherit the alleles on the Y chromosome? Only sons Which parent can pass on alleles on the X chromosome? Both mother and father Which child can inherit those alleles? Both sons and daughters Examples of different modes of inheritance in humans: ● autosomal recessive (homozygous) - hitchhiker's thumb (maybe), ability to taste PTC, cystic fibrosis, sickle cell anemia ● autosomal dominant (heterozygous) - achondroplastic dwarfism - dominant but rare, homozygous condition is fatal ● autosomal dominant (hetero or homo) Huntington’s disease – dominant but rare, homozygous condition leads to early appearance of symptoms, early death ● X-linked recessive – hemophilia ● X-linked dominant – Rett’s syndrome (fatal in XY boys) ABO blood type system: 2 copies of the “Blood type” gene in each person Three possible alleles, or variant forms: A, B, and O O is recessive A and B are both dominant with respect to O, and codominant to each other Human genome sequencing The entire genome of many humans has now been sequenced, as has the genome of a number of other animals and plants. For the humans, that means that every base pair has been identified in all 46 chromosomes. The human genome contains approximately 3 BILLION base pairs. This means we know the sequence of letters on all 46 chromosomes. It doesn’t mean we know what the words are, where the words begin and end, or what they ‘mean’ in terms of their effects – whether making a structural protein, or an enzyme, or being a controller gene. Imagine you came across pieces of an ancient text, in fragments, with some of the ink very faded and difficult to read, no spaces between the words, and in a foreign language you didn’t understand very well. You spend many hours cleaning the fragments, using chemicals and special lights to restore the faded ink, and then piecing the fragments together from the beginning of the book to the end. Finally, you have the entire text in order, in a form that is readable. That is where we stand now with the Human Genome Project. It will be many years, decades probably, before we figure out the spacing between the words, the punctuation, and the MEANING of the words. We do know what the book’s overall message is: This is how to build, operate/maintain, repair, and reproduce a human being. Non-coding DNA More than 95% of the genome is so-called “non-coding” DNA. Between the “genes” on the chromosomes are long stretches of DNA whose function is less well understood. This used to be called “junk” DNA. We know it includes the punctuation, the regulatory information, some of the switches, that control the other genes and their expression. Some of this non-coding DNA comes in the form of repetitions of long sequences, over and over. Like having the same sentence repeated in a book various numbers of times. It is estimated that only about 25,000 “genes” function to create and run a human being. Quadrupling of genome in vertebrate evolution: Vertebrates, including human beings, carry only around 25,000 genes (of the old, protein-building type). The rise of the vertebrates, some 520 million years ago, was marked by two separate doublings of the entire genome. Vertebrates have four times as many genes as their predecessors. These new genes were then available for mutations and selection and other genetic forces to operate on them. This gives rise to family of proteins, which are similar in structure and function, but not identical – like some of the 20 different proteins involved in blood clotting. This “gene duplication” (or quadruplification) plays an extremely important role in the evolution of biological complexity. Messenger RNA (mRNA) carries the information from inside the nucleus out into the cytoplasm to the place where Transfer RNA (tRNA) brings the amino acids and assembles the proteins RNA can also serve in regulatory capacities, and this noncoding RNA is also specified by genes on the chromosomes inside the nucleus. From genome to trait Most interesting traits are polygenic – many genes affect one trait; with multiple genes, each with varying numbers of alleles, contributing the genetic component, and then with the environment (from micro to macro) also contributing to the expression of the trait. And also some genes are pleiotrophic – meaning that one gene has many effects on many different structures or processes. The gene that turns on the testosterone-producing capability of the testes in males, for example. . . . Mutation A random change in the sequence of bases along the DNA strand. Usually occurs as a simple random change in the DNA sequence during chromosomal replication, either during meiosis or mitosis, but can also happen as a result of environmental factors. Most are neutral Many are negative, even fatal Some few are positive Evo Devo Evolutionary developmental biology Organisms show two kinds of change through time: ● during the lifetime of a single animal (egg to elderly adult) – ontogeny/embryology ● during the evolutionary history of a biological lineage (early primates to humans) – phylogeny The first kind of change can provide important insights into the second type of change. Ernst Haeckel’s law that “ontogeny recapitulates phylogeny” Laws of embryology – development proceeds from head to tail, and from the center to the periphery. Evo devo’s focus is on how different genes get switched on or off at different times in different cells in different tissues and organs. The answer is Hox (Homeobox) genes. Evo devo’s first big finding is that all animals are built from essentially the same genes. Evo devo is looking at the genes that control development – which end should be the head, and which the tail? Where should legs grow, versus antenna, how many of each, etc. Hox genes – genes that are expressed in different body parts that tell that part what appendages to grow. All animals have Hox genes, and nearly all animals use their Hox genes to determine which appendage should go where along the axis that runs from head to tail. The major animal groups have all been in place since the start of the Cambrian, so Hox genes must be at least half a billion years old. Several hundred genes, including the Hox genes, are needed to lay out an animal’s basic design. Known as “tool kit” genes – nearly all tool-kit genes are present in all animals and they do much the same thing in all animals. There is surprising genetic conservatism across many different kinds of animals – birds, jaguars, and humans are all built from the same basic set of genes. Evo devo’s second big finding is that different animal designs reflect the use of the same old genes, but expressed at different times and in different places in the organism. Tool kit genes are found in the noncoding DNA. They make proteins that toggle the switches on the regulatory genes near the protein-building genes. May be one toggle for: on or off in this type of cell or tissue May be one toggle for: on in children, off in adults “In effect, tool kit proteins act like molecular fingers, reaching out and physically turning on or off the switches that sit next to genes.” A single tool kit protein might switch many genes on or off. Evo devo’s third big finding is the claim that evolution is mostly a matter of throwing these switches. According to the evo devo perspective, animal evolution works not so much by changing genes (that make proteins) via mutations that result in different amino acids being inserted into the protein, but by changing when and where a conserved set of genes is expressed. Evolution is more regulatory (involving patterns of gene expression), and less structural (involving the precise proteins coded for by the genes). Of course, in reality, evolution is both.