WHEN... THERE!

When I first started this blog, I never thought I'd write an entire series on genetic history, and wanted to get done with it in 2-3 posts. As I progressed, I realized that I'd seriously underestimated the amount of information I had to cover. Looking back, I probably rushed through the first post-I should have elaborated on the events discussed, and have missed out on many important experiments in the 1900s. 

This post (and the following one) mainly addresses some of the experiments missed in that key blog post. The original will exist as a brief version, but this one is a detailed exploration ¹ of those experiments. 

So.

WELCOME FELLOW EXPLORERS and today's (and the following) post deals with the spicy 1900s- to be specific, developments from 1889- 1950. 

First, a picture of a chromosome so that we see where this is heading: 

(1) Chromatid ; (2) Centromere ; (3) Short arm (p) ; (4) Long arm (q).

We pick up after Mendel's Great Pea Experiment ². The result of this experiment was published in a relatively obscure scientific journal, and the scientific community lived in ignorance, not realizing the huge effect his discoveries had on genetics. Discussion and debate took place mainly on Darwin's theory of evolution based on natural selection, in which non-Lamarckian methods seemed to be required. Darwin's own theory of explaining the mechanism of inheritance- Pangenesis ³ - was inadequate and did not meet with a large degree of acceptance. Lamarckism was the theory given by Jean-Baptiste Lamarck, which proposed that organisms can pass on physical characteristics that the parent organism acquired through use or disuse during its lifetime to its offspring. Lamarckism and Pangenesis were disproved by August Weismann, who experimented by removing the tails of 68 white mice, repeatedly over 5 generations, and observed that no mice were born without a tail or even with a shorter tail. Weismann proposed the germ plasm theory of inheritance- that heritable information is transmitted only by germ cells in the gonads, not by somatic cells ⁴.

August Weismann.                                    Hugo de Vries. 

In 1889, Hugo de Vries ⁵, a Dutch botanist, published his book "Intracellular Pangenesis", in which, based on a modified version of Pangenesis, he postulated that different characters have different hereditary carriers. He postulated that the inheritance of specific traits in organisms comes in particles and called these units "pangenes"-a term which 20 years later was shortened to genes by Wilhelm Johannsen. To support his theory, which was not widely noticed at the time, de Vries conducted a series of experiments hybridizing varieties of multiple plant species. Unaware of Mendel's work, de Vries used the laws of dominance and recessiveness, segregation, and independent assortment to explain the 3:1 ratio of phenotypes in the second generation. His observations confirmed his hypothesis. In the late 1890s, de Vries became aware of Mendel's paper and he altered some of his terminologies to match. 

He then came up with his mutation theory, which was enormously influential, and the scientific community continued to be fascinated by it even after it was abandoned. Then in a published lecture in 1903, de Vries was the first to suggest the occurrence of recombinations between homologous chromosomes, now known as chromosomal crossovers, within a year after chromosomes were implicated in Mendelian inheritance.

Walter Sutton and Theodor Boveri independently hypothesized that chromosomes, which segregate in a Mendelian fashion, are hereditary units. Boveri was studying sea urchins when he found that all the chromosomes in the sea urchins had to be present for proper embryonic development to take place. Sutton's work with grasshoppers ⁶ showed that chromosomes occur in matched pairs of maternal and paternal chromosomes which separate during meiosis. He concluded that this could be "the physical basis of the Mendelian law of heredity." 

1902- Voilà! Mendel’s theories were associated with a human disease- alkaptonuria- by Sir Archibald Garrod, beginning our quest in understanding genetic disorders from errors in chemical pathways. Following this, William Bateson coined the term "genetics" in a letter to Adam Sedgwick and at a meeting in 1906! 

While we're at it, let's take a tiny detour. 

I'm pretty sure every biology enthusiast would have heard the phrase "...in Hardy-Weinberg equilibrium."

Love it or hate it, it's pretty important to biostatistics and population studies, particularly in areas where allele frequencies of a gene are studied. 

The Hardy-Weinberg Law, which was proposed independently by G. H. Hardy ⁷ and Wilhelm Weinberg, states that allele and genotype (the gene makeup of an organism) frequencies in a population will remain constant across generations in the absence of other evolutionary influences. In simple terms, it means the system has been practically isolated such that no random or drastic changes can take place. These changes include (among other things), natural selection and mutations too! Though that's surprising, it helps us evaluate populations and understand gene frequencies. 

Next up is our pioneering drosophilist, Thomas Hunt Morgan! Around 1908, Morgan started working on the fruit fly Drosophila melanogaster, and with Fernandus Payne, he mutated Drosophila through physical, chemical, and radiational means. He began cross-breeding experiments to find heritable mutations, but had no significant success for two years. In 1910, Morgan noticed a white-eyed mutant male among the red-eyed wild types. When white-eyed flies were bred with a red-eyed female, their progeny were all red-eyed. A second generation cross produced white-eyed males—a sex-linked recessive trait. In a paper published in Science in 1911, he concluded that 

(1) some traits were sex-linked, 

(2) the trait was probably carried on one of the sex chromosomes, and 

(3) other genes were probably carried on specific chromosomes as well.

Thomas Hunt Morgan. Did I mention he won the Nobel Prize in Physiology or Medicine? 

Morgan and his students became more successful at finding mutant flies; they counted the mutant characteristics of thousands of fruit flies and studied their inheritance. As they accumulated multiple mutants, they studied complex inheritance patterns. The observation of a miniature-wing mutant, which was also on the sex chromosome but sometimes sorted independently to the white-eye mutation, led Morgan to the idea of genetic linkage and to hypothesize the phenomenon of crossing over⁸. Morgan proposed that the amount of crossing over between linked genes differs and that crossover frequency might indicate the distance separating genes on the chromosome. Haldane suggested that the unit of measurement for linkage be called the morgan. Morgan's student Alfred Sturtevant developed the first genetic map in 1913.

In the following years, most biologists came to accept the Mendelian-chromosome theory by Sutton- Boveri and elaborated and expanded by Morgan and his students. Because of Morgan's dramatic success with Drosophila, many other labs throughout the world took up fruit fly genetics. Drosophila became one of the first, and for some time the most widely used, model organisms. 

"The single most important figure in 20th century statistics"

"A genius who almost single-handedly created the foundations for modern statistical science"
"The greatest of Darwin’s successors" (for his contributions to biology)

A British polymath and biologist who was a mathematician, statistician and geneticist? 

Guess who I'm talking about?

It's Sir Ronald Fisher. 

Sir Ronald Fisher.

In 1918, he published "The Correlation Between Relatives on the Supposition of Mendelian Inheritance". In it, Fisher puts forward the "infinitesimal model", a model showing that continuous variation amongst phenotypic traits could be the result of Mendelian inheritance. It is based on the idea that variation in a quantitative trait is influenced by an infinitely large number of genes, each of which makes an infinitely small contribution to the phenotype, as well as by environmental factors. 

The paper also contains the first use of the term variance (Variance is the expectation of the squared deviation of a random variable from its population mean or sample mean. It is basically a measure of how far a set of numbers is spread out from their average value.)

This paper laid the foundation of the modern synthesis of genetics and evolutionary biology, which was the early 20th century synthesis linking Darwin's theory of evolution and Mendel's work on heredity to population genetics and observations of macro and microevolution.    

Fisher's contribution to biology was huge- he is known as one of the three principal founders of population genetics. He outlined Fisher's principle, the Fisherian runaway and theories of sexual selection. His contributions to statistics include promoting the method of maximum likelihood and deriving the properties of maximum likelihood estimators, fiducial inference, the derivation of various sampling distributions, founding principles of the design of experiments, and much, much more⁹.

On that note, we come to the end of our affair with genetics in the late 19th and early 20th centuries, and next week we start with the magical years post 1923- see you there!

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¹ Evolution & Natural Selection has its' own series coming up (stay tuned!), so the briefing on Mendel and Darwin is sufficient for now. 

² The detailed explanation regarding basic concepts behind genetics (Mendel's Crosses, Darwinism etc.) will again, will be compiled in another series (stay tuned!) and basic information regarding these concepts is sufficient for now.

³ Pangenesis was Charles Darwin's hypothetical mechanism for heredity, in which he proposed that each part of the body continually emitted its own type of small organic particles called gemmules that aggregated in the gonads, contributing heritable information to the gametes (Yes this definition is from Wikipedia.)

⁴ For those of you who do not know what 'germ cells' and 'somatic cells' mean, here's a brief. Germ cells are basically cells that produce gametes of an organism that reproduces sexually. They divide through the process of meiosis- where there are 2 rounds of division and 4 cells are produced, each being haploid (they have half the normal number of chromosomes in a cell- this is because during fertilization, the male and female gametes fuse, and this maintains the chromosome number.) All other cells of the body replicate through the process of mitosis- where there is only 1 round of division, 2 cells are produced, each being diploid (they have the normal number of chromosomes since somatic cells form the building blocks of the body and are also used for repair)- and are called somatic cells. 

⁵ Interesting story here- Correns and Erich von Tschermak now share credit for the rediscovery of Mendel’s laws. Correns was a student of Nägeli, a renowned botanist with whom Mendel corresponded about his work with peas but who failed to understand its significance, while, coincidentally, Tschermak's grandfather taught Mendel botany during his student days in Vienna. 

⁶ Plus, Eleanor Carothers documented definitive evidence of independent assortment of chromosomes in a species of grasshopper.

⁷Again, interesting story- Udny Yule (the guy famous for Yule distributions) argued against Mendelism because he thought that dominant alleles would increase in the population. Reginald Punnett (Yes, the guy famous for the Punnett Square), unable to counter Yule's point, introduced the problem to G. H. Hardy (among other things, the guy famous for mentoring Srinivasa Ramanujan), with whom he played cricket.

⁸ He relied on the discovery of Frans Alfons Janssens, a Belgian professor at the University of Leuven, who described the phenomenon in 1909 and had called it chiasmatypie.

⁹ Yes, I don't completely understand half the things too :D: https://en.wikipedia.org/wiki/Ronald_Fisher#Legacy