Pedigree, Genetic Disorders, and Mutations

Pedigrees, Genetic Disorders, and Mutations

Genetic Mutation:

A genetic mutation is a change in a sequence of your DNA. Your DNA sequence gives your cells the information they need to perform their functions. If part of your DNA sequence is in the wrong place, isn’t complete or is damaged, you might experience symptoms of a genetic condition.¹ 

A mutagen-a chemical or physical agent capable of inducing changes in DNA called mutations. We will study more of how this happens when we discuss the structure of DNA, but chemicals, viruses, bacteria, and radiation can cause mutation of genes.  When the gene is mutated, the protein it codes for will not be shaped correctly, and may function poorly or not at all.

Most often, genetic mutations occur during cell division, not from a mutagen. They can be caused by a mutagen or by simple error.  When your cells divide, they hand-write your body’s instruction manual by copying the original document word for word. There’s a lot of room for error during cell division because your cells might substitute (replace), delete (remove) or insert (add) letters while they’re copying. If you have an error (genetic mutation), your genetic instruction manual for your cells may not be readable by the cells, or may have missing parts or unnecessary parts added. All of this can mean that your cells can’t function as they normally should. Somatic mutations occur in our autosomes.  Germ-line mutations happen in our sex chromosomes. 

Discussion: 

Are genetic mutations good or bad?

Examples of beneficial genetic mutation:

APO-AIM- There are beneficial cholesterols (HDL's) that remove deposits from your arteries, and harmful cholesterols(LDL) that  basically will clog your arteries.  Alipoprotien-IA is a beneficial choslesterol.  THere is a small community of Italians who have a genetic mutation of of Alipoprotien-IA Milano, which is super good at removing bad cholesterol.  THey absorb it and carry it back to the liver. It also prevents inflammation and hardening of the arteries.  People with this mutation have a significantly lower risk of heart disease.

Increased Bone Density- Mutations of LRP5- a prtien receptor- cause osteoperosis genetically.  You can get osteoperosis environmentally as well. However, another mutation of LRP5 goes the other direction.  Your bones are more dense. THis was discovered after a young man in a serious car crash in Ohio walked away with no broken bones.  They studied his family and found he and other members of his family had extremely dense bones and had never experienced a broken bone.  Their bones didn't even experience age related osteoperosis which almost 100% of people experience to some degree.  Bad side effect, its harder to float and swim. 

Sickle-cell- People with  one copy of the gene for hemoglobin (HbC), a version of sickle-cell,  are 29% less likely to get malaria.  People with two copies of the gene are 93% less likely to get malaria. This version of sickle-cell is very mild, and doesn't experience the terrible symptoms of full blown sickle-cell anemia. This was studied in the African Nation Burkina, where malaria is a frequent threat to human life.

Tetrachromatic vision- We know that color vision is an X-linked trait and that men more often get colo-blindness, because they don't have another X allele to mask the recessive allele for color blindness.  THe eyes have rods, that see at low light levels with no color, and cones that see at high light level with color vision. Chromosome 7 codes for cones that see blue.  The X chromosome carries the gene that codes for cones that see Red and Green.  A "tetrachromat" has a mutation coding for a fourth color, like birds and turtles.  Do they see a color we don't know or understand....possibly!  They deffintely can see shades of colors that we can not discern. 

PEDIGREES

When you are talking about a pedigreed dog, it means the dog is purebred. Through selective breeding, the dog has all the traits of that particular breed. They are breed generation after generation for particular traits, and having a trait that is not part of that "standard" for the breed, disqualifies the dog for breeding.  The American Kennel Association is one of the organizations that determines the standard for a breed.  For a new dog breed to be considered for being an accepted standard by AKC, there must be  a demonstrated following and interest (minimum of 100 active household members) in the breed (in the form of a National Breed Club). A sufficient population in this country (minimum of 300-400 dogs), with a three-generation pedigree. Dogs in that pedigree must all be of the same breed.  This is an intentional selection of bredding partners to get a particular genotype and phenotype.

We use a very similar chart  to record and research our own genealogy. Here is the genealogy chart of President Theodore Roosevelt and President Franklin Delano Roosevelt, 26th and 32nd Presidents of the united states. 

When talking about genetics, however, a pedigree is a chart that helps show family relationships. Scientists use standardized methods to construct pedigrees.  These are charts of genetic connections among individuals.  Pedigrees are analyzed to determine whether the inheritance of certain traits follows patterns through generations. The chart in the image is called a pedigree. It shows how the earlobe trait was passed from generation to generation within a family.

In a pedigree, squares symbolize males, and circles represent females. A horizontal line joining a male and female indicates that the
couple had offspring. Vertical lines indicate offspring which are listed left to right, in order of birth. Shading of the circle or square indicates an
individual who has the trait being traced. In this pedigree, the inheritance of the recessive trait is being traced. A is the dominant allele, and a is the recessive
allele. 

It is easy to study pea plants and fruit flies, but humans are not so easy. We select our own mates. We live in variable conditions and diverse environments. We reproduce when and if we want. Most people have small families, so it would be hard to make inferences about genetic probability.  Human subjects may live longer than the geneticist studying them, so tracking peoples genetics long term is more difficult than short lived organisms. Often genetic inheritance can be traced through a pedigree chart, helping Doctors determine its frequency in a population, what chromosomes genes may be linked to, and how mutations express themselves.  Below is a chart for polydactyly, extra fingers and toes. Ectrodactyly is missing fingers.  The gene for Polydactyly is rare but dominant.  There are places in the word where it is more common, and species where it is more common, such as cats. 

Pedigree charts have been widely used to study historical figures, as we can't test their DNA now, but we can search the records of history  to see which individuals in a family tree had the studied trait.  This has been done extensively with the Family Tree of Royals in Europe, England, and Russia. 

The case of the Blue Fugates

Methemoglobinemia occurs when red blood cells (RBCs) contain methemoglobin at levels higher than 1%. Methemoglobin results from the presence of iron in the oxidized ferric form (Fe³⁺) instead of the usual reduced ferrous form (Fe²⁺). This results in a decreased availability of oxygen to the tissues. This condition can be congenital or acquired. 

Symptoms are proportional to the methemoglobin level. At levels up to 20%, changes can occur in the color of blood and skin. For nearly 200 years, the Fugates — known as the blue people of Kentucky — remained largely sealed off from the outside world as they passed their blue skin from generation to generation. Unbeknownst to either of them, by some incalculable odds, both possessed a recessive gene that led to four of the seven children of this union being born with blue skin. In those days in rural eastern Kentucky, there were no roads, and a railroad wouldn’t even reach that part of the state until the early 1910s. As a result, many of the Fugates began to marry and have children within their own bloodline. This kind of genetic isolation allowed for the continued reproduction and expression of the Fugate family’s “blue skin” gene.

HUMAN GENETIC DISORDERS

The following genetic disorders have been studied with pedigree charts. 

Autosomal Recessive Inheritance

Albinism- the absence of pigment. The enzyme produced by the TYR gene, called tyrosinase, is required for the synthesis of melanin pigment. A mutation in the TYR gene causes the most common form of albinism. People with albinism have either a partial or complete lack of pigment, or coloring, in their eyes, skin or hair.

This girl also has heterochromia- different colored eyes which can be genetic, a rare autosomal dominant trait, or can be more often caused by eye injury in utero.  Little cells called melanocytes, which make pigment don't get to the right site in the iris.  If the cause is genetic it is usually a syndrome, so more than one trait is affected, for instance a person might have heterochromia and be deaf.  Heterochromia is a common thing in some breeds of dogs, and this is definitely genetic. It can also happen in humans with Chimerism, which is greek name for a mythical animal with both a goat and lions head.  A human chimera is made up of cells from two different sources- so having two distinct sets of DNA.  This is when a one of a set of twins dies in utero and its cells are absorbed into the remaining twin.  Organ transplantation, blood marrow donation is another way to become a chimera.  People usually don't know they are a chimera unless a genetic abnormaility comes up....like DNA testing your children and finding they appear genetically to be a neice or nephew.  

 Sickle Cell Anemia- sickle shaped hemoglobin that clogs blood vessels. Jaundice, yellow skin,  is common because good blood cells break down more quickly than they should.  

Galactosemia- infants that can't digest breast milk. The enzymes that break down galactose- a sugar in breast milk, or lactose a sugar in formula, are not shaped correctly. It is life threatening if a baby has it, causing cataracts, liver and kidney disease. It is simple to treat and diagnose.  A newborn baby is given a heal prick blood test right after they are born. They are given soy-based formula instead and a diet to avoid dairy. 

Phenylketonuria (PKU)- a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. PKU is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. Again, diagnosed with a heal prick right at birth, the parents will be given information and counseling on a low protein diet. 

Autosomal Dominant Inheritance:

Achondroplasia- Dwarfism-a form of short-limbed dwarfism. The word achondroplasia literally means "without cartilage formation." Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. However, in achondroplasia the problem is not in forming cartilage but in converting it to bone (a process called ossification), particularly in the long bones of the arms and legs. Dwarfism is considered less than 4 ft 10 inches once adult stature is reached. 

X-linked Inheritance:

Hemophilia A- deficient blood clotting

Changes in Chromosome Structure:

Cri-du-chat- mental disability, skewed larynx- "cats cry"Cri-du-chat (cat's cry) syndrome, also known as 5p- (5p minus) syndrome, is a chromosomal condition that results when a piece of chromosome 5 is missing . Infants with this condition often have a high-pitched cry that sounds like that of a cat.

Changes is Chromosome Number:

Downs Syndrome- Heart Defects, mental disability- #21 trisomy. Down syndrome is a genetic disorder caused when abnormal cell division results in extra genetic material from chromosome 21. Down syndrome causes a distinct facial appearance, intellectual disability, developmental delays, and may be associated with thyroid or heart disease.

Turners Syndrome- a condition that affects only females, results when one of the X chromosomes (sex chromosomes) is missing or partially missing. Turner syndrome can cause a variety of medical and developmental problems, including short height, failure of the ovaries to develop and heart defects.