Unit 4: What Everyone Should Know About the Human Genome
Unit 4: What Everyone Should Know About the Human Genome
“DNA… What Is a Gene?… Three Surprising Findings From the Human Genome Project… Genetic Variation.. Williams Syndrome… The X Chromosome… Prader-Willi & Angelman Syndromes… Genetic Regulation and Epigenetics… Supplemental – Epigenetic Inheritance… ”
Module C: Three Surprising Findings From the Human Genome Project
Module D: Genetic Variation
Module E: Williams Syndrome
Module F: The X-Chromosome
Module G: Prader-Willi & Angelman Syndromes
Module H: Genetic Regulation and Epigenetics - UPDATED
Module I: Supplemental - Epigenetic Inheritance
Module A: DNA
DNA is comprised of two sugar phosphate backbones that are connected with hydrogen bonds that form between the four nucleotides bases adenine (A), thymine (T), guanine (G), and cytosine (C).
The hydrogen bonds – there is a constrained pairing between the bases on the two backbones e.g adenine (A) pairs with thymine (T), whereas guanine (G) pairs with cytosine (C).
DNA unwinds its helical form during replication, and because of the constrained pairing, each strand serves as a template for the synthesis of a complimentary strand (because A pairs with T, and G pairs with C).
Most DNA is found within the nucleus of every cell, and long strands of DNA packaged with proteins become chromosomes.
DNA functions as the code for life in the form of protein.
This happens via the central dogma of molecular biology: DNA -> RNA -> Protein
Transcription: Double stranded DNA (double stranded nucleic acid) is transcribed into single stranded RNA (ribonucleic acid); RNA nucleotide bases are like DNA’s except that uracil (U) substitutes for thymine (T).
Translation: The RNA becomes the template to construct a protein. In a translation process, the basic informational unit is packed in 3 nucleotide bases, termed as a codon, and each codon spells out single amino acid (there are 20 amino acids, so we need at least 3 bases).
The two strands of DNA: one is called the sense strand, and the other the antisense strand. The former looks like the RNA that results from transcription (except the T is replaced by U), while the antisense strand is used as the template – because of constrained pairing – to construct the RNA.
DNA is the code for life in the form of proteins, which are chains of amino acids – look into this process a little more closely.
Recall that DNA is double stranded, and in books etc the sequence of a gene is usually shown as the sense strand of the DNA.
There’s an orientation to a gene:
Five prime (5′) end is called the upstream end;
Three (3′) prime end is called the downstream end of a gene.
How does it know what to transcribe?
Gene is transcribed from five prime end to three prime end
Upstream end of a gene contains regulatory region, and it is a promoter region which tells the transcription process where to start the transcription, but is not translated.
Between the upstream and downstream ends, the gene is not continuous – they contain:
Exons (the regions that are transcribed and translated i.e. expressed regions of DNA); and
Introns (regions transcribed but not translated i.e. intervening sequences).
Example using beta hemoglobin gene – a gene with 146 amino acids – that is involved in sickle cell anemia. It has three exons, two introns, and two untranslated regions (on the first and last exons).
Module C: Three Surprising Findings From the Human Genome Project
Human Genome Project – an international collaboration that begun in 1990 with countries all across the world participating in sequencing the human genome.
There are approximately 3.2 billion base pairs of gene in human.
Geneticists call a thousand bases as a kilo-base.
A million bases of DNA is a mega-base
A billion bases is a giga-base.
First surprise: most of the genome is not involved in the primary function of DNA – only about 1.5% of the 3.2 billion bases of DNA is involved in coding for protein, most of the genome ~98% is not (likely to have some function regulating the protein coding segment of DNA).
Second surprise: humans have a relatively small number of protein-coding genes, ~21,000 of them; because of this, we now have a modern definition of the gene:
“Classic” definition: a sequence of DNA (a locus on a chromosome) that is involved in (“codes for”) the synthesis of a functional polypeptide (proteins consist of one ore more polypeptides);
“Modern” definition: A locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions and/or other functional sequence regions.
In short, a gene is is any functional sequence in the DNA that somehow has function on our phenotype.
Third surprise: humans share more than 98% of DNA chimpanzee; and two humans share 99.9% of DNA.
0.1% of 32 billion bases is different, which is 3.2 million differences per strand, which gives about 6 million differences over double strands.
Two humans will still differ at 6 million bases/locations in the genome.
And very small changes in our DNA can have significant effect on phenotype (e.g. cystic fibrosis).
0.1% or 6 million base differences between any two random individuals.
Recap on terminology:
Allele(s) – alternative form(s) for a gene at a location/locus;
Polymorphism – genetic differences common in the population (allele frequency > 1%);
Mutations – genetic differences rare in the population (allele frequency < 1%);
Genetic variants – genetic differences including polymorphisms and mutations.
Three types of Genetic variation:
Sequence: difference in the bases at a specific location;
Structure: difference in the number of bases of DNA;
Organization: difference in how the DNA is packed or organized
Genetic variation in sequence (most common): SNPs i.e. single nucleotide polymorphisms e.g. beta-hemoglobin gene where the sickle cell anemia phenotype is actually a SNP where a mutation has occurred that changes the DNA base T to A.
Examples of genetic variation in structure (fairly rare):
Variable Number of Tandem repeats (VNTR) and Huntington Disease;
Extra and missing DNA:
insertion/deletion of a small number of bases;
insertion/deletion of large number of bases (Copy Number Variants – CNVs);
extra or missing chromosome (aneuploidy) e.g. Down’s Syndrome.
Examples of genetic variation in organization are translocations and inversions; there are not many behavioral examples of the variation’s effects at this point.
Williams Syndrome: 1.5 – 1.8 million bases of DNA have been deleted from the long arm of chromosome 7.
Individuals with Williams syndrome:
suffer from aortic stenosis that results in constricted aorta and subsequently hypertension and high blood pressure;
have distinctive facial features like elfin-like faces, delicate chins and large mouths;
suffer from intellectual disabilities;
have relatively intact verbal and linguistic abilities;
but lack of visual-spatial abilities;
difficulty integrating the parts into a whole;
Behaviourally, they
are extremely friendly and very happy people, in fact hyper social;
have sensitive hearing, termed hyperacusis;
interested in musical pursuits.
They have existed throughout history, but it is only now that we understand them better; in fact they might have been the inspiration for elves and leprechauns (happy, musical, hyperacusis represented by large years).
In humans, there is an X chromosome and a Y chromosome, and the other 22 chromosome pairs.
X and Y results in a genetically male individual whereas two Xs results in a female.
The X chromosome has about 2000 genes and 155 million or mega bases of DNA
The Y chromosome has only about 80 genes and is about one third of the size of an X chromosome.
But it does not mean the two Xs in the female produce twice as much compared to the men as only one X chromosome is active, the other one is inactivated
The inactivation of one of the X’s occurs early in embryonic development, and the inactivation is permanent in all daughter cells.
Module H: Genetic Regulation and Epigenetics – UPDATED
An example of long term genetic regulation: see discussion on X chromosome in Module F – every cell that derives from that initial cell will have the same X chromosome inactive.
Second example: imprinting – see discussion in Module G – where the gene expression is dependent on gender of the parent who passed on the gene.
Third example: in every nucleus of every cell in our body, we have the same DNA but our body is made up of many different types of cells like muscle cells, neurons, liver cells etc – an embryonic stem cell is a stem cell that has the potential to express any one of the 20,000 plus genes in the human genome.
Epigenetics (Greek for “on top of genes) is the study of genetic regulation, where there are stables changes in gene expression that are not because of differences in the DNA sequence.
Many of the mechanisms of epigenetic control actually involve gaining access to the DNA in the cell nucleus – the mechanism we have the most knowledge of is DNA methylation.
Methylation involves adding a methyl group to bases: when a methyl group is attached to the promoter region, it blocks the transcription of the gene.
Three class studies:
Medical phenotype: Agouti mouse is a mouse that has ravenous appetite, they overeat so they become obese – feeding pregnant mice with a diet rich in methyl groups (e.g. broccoli and lentils) resulted in the mice giving birth to mice that did not overeat.
Behavioral phenotype: removal of rat pups from their mother during early stage in life for a short period, and then placing them back, led to the pups being less anxious or fearful as rat adults; turns out it is because the mother would groom the pups upon the reintroduction, and that demethylated and turned on the gene that helped them be less anxious later as adults.
Dutch Hunger Winter study: Individuals who experienced malnourishment at the very early stage of embryonic development – disrupting the methylation and demethylation of key genes – experienced long-term consequences such as higher body mass index, higher rates of obesity, disrupted glucose metabolism or even higher risks of schizophrenia.
Epigenetics: Stable changes in gene expression that are not due to the sequence of DNA an individual has.
The examples in the previous Module show stability over mitosis; are epigenetic markings also stable over meiosis i.e. pass on from one generation to the next?
Study of Overkalix, Sweden: small region with excellent records clearly showing when the population went through periods of feast and famine through the 19th century. Results showed:
If grandparents had lots of food in a period before puberty, their grandsons and granddaughters had a higher rate of mortality;
But only true for paternal transmission;
Speculation that the reasons are epigenetic.
Important to see that there has to be epigenetic reprogramming e.g. a sperm cell and an egg cell have different epigenetic profiles but when they come together, the cells are going to derive from that embryo are going to have all different types of gene expression patterns.
If there is epigenetic inheritance, it has to survive the above epigenetic programming.
Study of mice and odor conditioning (so that they would fear a particular door) and how that is passed on to the offspring.
A lot of debates over epigenetics e.g. is it rare or general?
This partly explains the interest in research in epigenetics and twins: monozygotic twins are genetically identical but they are not psychologically the same – is this because of epigenetics i.e. same genome but different epigenome?
Explanation of a study of global epigenetic methylation of monozygotic twins’ chromosomes, and how they are more similar when they are younger than when they are much older.
