Concept

Although Mendel's laws were first tested in pea plants and fruit flies, evidence quickly mounted that they applied to all living things. Just as mutations had provided keys to understanding fruit fly genetics, pedigrees of families affected by diseases provided many of the first examples of Mendelian inheritance in humans. Recessive inheritance was first described for the disorders alkaptonuria (1902) and albinism (1903). Among the first dominant disorders discovered were brachydactyly (short fingers, 1905), congenital cataracts (1906), and Huntington's chorea (1913). Duchenne muscular dystrophy (1913), red-green color blindness (1914), and hemophilia (1916) were the first sex-linked disorders. The simple concept of eye color inheritance — brown is dominant, blue is recessive — was published in 1907; however, scientists now believe that several genes are involved.

Animation

We shall tell you about pedigrees; ours is most detailed. We will focus on that part of the family line leading up to the Russian Royal House – the Romanovs. Pedigrees are most useful for tracing lineage, and since the mid-1800's (during my reign), pedigrees have been adapted for tracking human genetic heredity. Females are represented by circles; Females are represented by circles, males by squares. A horizontal line connects those who marry … … and vertical lines lead to children begotten from the marriage. Albert, my dear Prince Consort and I, had nine children for the glory of England. To our sorrow, our line was tainted with the royal bleeding disease, hemophilia. Since the early 1800's, hemophilia was believed to be an inherited disease affecting males. I did not have hemophilia, but it seemed that I carried and thus passed the trait to my descendants. In a genetic pedigree, individuals known to be affected by a trait are filled squares (or circles). Carriers are dotted. I, Queen Victoria, was a hemophilia carrier. Of our nine children, poor Leopold had hemophilia. We know Alice and Beatrice were carriers because hemophilia was seen in their male children. Of my grandchildren from Alice, one had hemophilia, two were unaffected and two were carriers. 'Twas most unfortunate, my granddaughter, Alexandra, was a carrier. She married Nicholas Romanov II, Czar of Russia. They had five children. My great grandson, the heir Alexis, had hemophilia. Tragically, the whole family was killed in 1918 by the Bolsheviks during the Russian revolution. You may be more familiar with this story if I told you that one of Alexis' sisters was Anastasia. Of course, since the whole family was killed, it is not known if any of Alexis' sisters were carriers for hemophilia. If you look at our pedigree, only the princes are affected and some of the princesses are carriers. This, we've been told, is a classic example of sex-limited or sex-linked recessive inheritance. A sex-linked trait is on the X chromosome. Females have two X chromosomes; they can inherit/carry the trait without being affected if it acts in a recessive manner. Hemophilia is just such a trait. Males only have one X chromosome so if they inherit the affected X, they will have the disorder – just like poor little Alexis. Follow my affected X chromosome through our pedigree. I'm Charles Davenport. In 1907, I published the genetics of eye color. Dark eye colors are inherited in a dominant manner. Light eye colors are inherited recessively. Let me show you. We start with a brown-eyed woman whose whole family has had brown eyes for several generations. She is homozygous for brown eyes. She marries a blue-eyed man whose whole family has had blue eyes for several generations. He is homozygous for blue eyes. They will have children with brown eyes. Brown is the dominant eye color. If one of their heterozygous children marries a person also heterozygous for eye color, most of their children will have brown eyes but some will have blue eyes. The proportion of brown to blue eyed children will be 3:1; just like the dominant vs. recessive ratio Mendel observed in his pea plants. In a pedigree, dominantly inherited traits, for example brown eyes, can look like this. Pedigrees of recessive traits, for example blue eyes, can look like this. Notice how the trait skipped a generation. Human genes do follow Mendelian laws. However, humans are not peas. Although, I tried to explain eye color inheritance as a single gene system, scientists now believe that two or three genes are involved in eye color determination. Also, the particular shades of an eye color may be a result of the variable expression of these genes in an individual.

Gallery

Sir Archibald Edward Garrod, around 1910.

Colonel Archibald Edward Garrod in his World War I uniform.

(P. 1 of 3) Letter from T.H. Morgan to Charles Davenport about Mohr's work on brachydactyly.

(P. 2 of 3) Letter from T.H. Morgan to Charles Davenport about Mohr's work on brachydactyly.

Audio/Video

Audio Glossary

Dominant, Enzyme, Pedigree, Recessive, Sex-linked

Video Interviews

Garland Allen

Garland Allen is a Professor in the Evolutionary and Population Biology Program at Washington University in St. Louis. He authored Thomas Hunt Morgan: The Man & His Science, and several texts, including Matter, Energy and Life and The Study of Biology.

Clip 1 (1:01)
Mendelian theory and its use by experimental evolutionists.

Biography

Archibald Garrod was the first to connect a human disorder with Mendel's laws of inheritance. He also proposed the idea that diseases came about through a metabolic route leading to the molecular basis of inheritance.

SIR ARCHIBALD EDWARD GARROD (1857-1936)

Archibald Garrod was the son of the physician, Alfred Baring Garrod, who diagnosed and studied rheumatoid arthritis. Although his father initially intended for Archibald to study business, his teachers recognized and encouraged him to go into the field of science and medicine. Garrod studied medicine at Oxford University and became a physician.

Garrod was studying the human disorder alkaptonuria. He collected family history information (as well as urine) from his patients. Based on discussions with Mendel advocate William Bateson, Garrod deduced that alkaptonuria is a recessive disorder. In 1902, Garrod published a book called The Incidence of Alkaptonuria: a Study in Chemical Individuality. This is the first published account of a case of recessive inheritance in humans.

Garrod was also the first to propose the idea that diseases were "inborn errors of metabolism." He believed that diseases were the result of missing or false steps in the body's chemical pathways. In 1923, his studies on alkaptonuria, cystinuria, pentosuria, and albinism were published as a book: Inborn Errors of Metabolism. Garrod attributed a biochemical role to genes, and laid the groundwork for the next wave of discovery -- the molecular basis of inheritance.

Garrod was more of a scientist than a physician. His bedside manner was said to be limited to his interest in his patients' urine samples. Garrod did have a strong sense of duty and served as a colonel in Malta in World War I. He was knighted in 1918. The death of two of his sons in the war and of a third son (his last) in the post-war influenza epidemic was a sad blow in the later years of Garrod's life.

Links

National Human Genome Research Institute (NHGRI)

NHGRI was established in 1989 to head the Human Genome Project for the National Institutes of Health. They have a searchable glossary of genetic terms and a news section on topics relating to molecular genetics and genome sequencing projects.

Blazing a Genetic Trail

This is the The Howard Hughes Medical Institute site on genetics and molecular biology. It has a section on the genetics of Huntington's disease and cystic fibrosis.

Bibliography

Bearn, Alexander G., 1993, Archilbald Garrod and the Individuality of Man, Clarendon Press, Oxford.
Knox, W., Eugene, 1967, Sir Archibald: a Biography, Genetics, 56: 1-6, Genetics Society of America.
Rushton, Alan R., 1994, Genetics and Medicine in the United States 1800 to 1922, Johns Hopkins University Press, Baltimore.

Glossary

Dominant - A gene that almost always results in a specific physical characteristic, for example, a disease, even though the patient's genome possesses only one copy. With a dominant gene, the chance of passing on the gene (and therefore the disease) to children is 50-50 in each pregnancy.
Enzyme - A protein that encourages a biochemical reaction, usually speeding it up. Organisms could not function if they had no enzymes.
Pedigree - A simplified diagram of a family's genealogy that shows family members' relationships to each other and how a particular trait or disease has been inherited.
Recessive - A genetic disorder that appears only in patients who have received two copies of a mutant gene, one from each parent.
Sex-linked - Located on the X chromosome. Sex-linked (or x-linked) diseases are generally seen only in males.

Children resemble their parents.
Genes come in pairs.
Genes don't blend.
Some genes are dominant.
Genetic inheritance follows rules.
Genes are real things.
All cells arise from pre-existing cells.
Sex cells have one set of chromosomes; body cells have two.
Specialized chromosomes determine gender.
Chromosomes carry genes.
Genes get shuffled when chromosomes exchange pieces.
Evolution begins with the inheritance of gene variation.
Mendelian genetics cannot fully explain human health and behavior.
DNA and proteins are the molecules of the cell nucleus.
One gene makes one protein.
A gene is made of DNA.
Bacteria and viruses have DNA too.
The DNA molecule is shaped like a twisted ladder.
A half DNA ladder is a template for copying the whole.
RNA is an intermediary between DNA and protein.
DNA words are three letters long.
A gene is a discrete sequence of DNA nucleotides.
The RNA message is sometimes edited.
Some viruses store genetic information in RNA.
RNA was the first genetic molecule.
Mutations are changes in genetic information.
Some types of mutations are automatically repaired.
A chromosome is a package for DNA.
Higher cells incorporate an ancient chromosome.
Some DNA does not encode protein.
Some DNA can jump.
Genes can be turned on and off.
Genes can be moved between species.
DNA responds to signals from outside the cell.
Different genes are active in different kinds of cells.
Master genes control basic body plans.
Development balances cell growth and death.
A genome is an entire set of genes.
Living things share common genes.
DNA is only the starting point for understanding human biology.
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