Margaret Oakley Dayhoff

Margaret Belle (Oakley) Dayhoff (March 11, 1925 – February 5, 1983) was an American physical chemist and a pioneer in the field of bioinformatics.

Dayhoff was a professor at Georgetown University Medical Center and a noted research biochemist at the National Biomedical Research Foundation, where she pioneered the application of mathematics and computational methods to the field of biochemistry.

She dedicated her career to applying the evolving computational technologies to support advances in biology and medicine, most notably the creation of protein and nucleic acid databases and tools to interrogate the databases.

She originated one of the first substitution matrices, point accepted mutations (PAM).

The one-letter code used for amino acids was developed by her, reflecting an attempt to reduce the size of the data files used to describe amino acid sequences in an era of punch-card computing.

Her PhD degree was from Columbia University in the department of chemistry, where she devised computational methods to calculate molecular resonance energies of several organic compounds.

Her academic promise was evident from the outset – she was valedictorian (class of 1942) at Bayside High School, Bayside, New York, and from there received a scholarship to Washington Square College of New York University, graduating magna cum laude in mathematics in 1945 and getting elected to Phi Beta Kappa.

Dayhoff began a PhD in quantum chemistry under George Kimball in the Columbia University Department of Chemistry.

In her graduate thesis, Dayhoff pioneered the use of computer capabilities – i.e. mass-data processing – to theoretical chemistry; specifically, she devised a method of applying punched-card business machines to calculate the resonance energies of several polycyclic organic molecules.

Her management of her research data was so impressive that she was awarded a Watson Computing Laboratory Fellowship.

As part of this award, she received access to "cutting-edge IBM electronic data processing equipment" at the lab.

After completing her PhD, Dayhoff studied electrochemistry under Duncan A. MacInnes at the Rockefeller Institute from 1948 to 1951.

In 1952, she moved to Maryland with her family and later received research fellowships from the University of Maryland (1957–1959), working on a model of chemical bonding with Ellis Lippincott.

At Maryland, she gained her first exposure to a new high-speed computer, the IBM model 7094.

They actually began this work in 1958, but were not able to start programming until late 1960.

She did postdoctoral studies at the Rockefeller Institute (now Rockefeller University) and the University of Maryland, and joined the newly established National Biomedical Research Foundation in 1959.

She was the first woman to hold office in the Biophysical Society and the first person to serve as both secretary and eventually president.

Dayhoff was born an only child in Philadelphia, but moved to New York City when she was ten.

After this ended, she joined the National Biomedical Research Foundation in 1960 as associate director (a position she held for 21 years).

At the NBRF, she began to work with Robert Ledley, a dentist who had obtained a degree in physics and become interested in the possibilities of applying computational resources to biomedical problems.

He had authored one of the earliest studies of biomedical computation, "Report on the Use of Computer in Biology and Medicine."

In the early 1960s, Dayhoff also collaborated with Ellis Lippincott and Carl Sagan to develop thermodynamic models of cosmo-chemical systems, including prebiological planetary atmospheres.

She developed a computer program that could calculate equilibrium concentrations of the gases in a planetary atmosphere, enabling the study of the atmospheres of Venus, Jupiter, and Mars, in addition to the present day atmosphere and the primordial terrestrial atmosphere.

Using this program, she considered whether the primordial atmosphere had the conditions necessary to generate life.

Although she found that numerous small biologically important compounds can appear with no special nonequilibrium mechanism to explain their presence, there were compounds necessary to life that were scarce in the equilibrium model (such as ribose, adenine, and cytosine).

With their combined expertise, they published a paper in 1962 entitled "COMPROTEIN: A computer program to aid primary protein structure determination" that described a "completed computer program for the IBM 7090" that aimed to convert peptide digests to protein chain data.

In 1966, Dayhoff pioneered the use of computers in comparing protein sequences and reconstructing their evolutionary histories from sequence alignments.

To perform this work, she created the single-letter amino acid code to minimize the data file size for each sequence.

This work, co-authored with Richard Eck, was the first application of computers to infer phylogenies from molecular sequences.

It was the first reconstruction of a phylogeny (evolutionary tree) by computers from molecular sequences using a maximum parsimony method.

In later years, she applied these methods to study a number of molecular relationships, such as the catalytic chain and bovine cyclic AMP-dependent protein kinase and the src gene product of Rous avian and Moloney murine sarcoma viruses; antithrombin-III, alpha-antitrypsin, and ovalbumin; epidermal growth factor and the light chain of coagulation factor X; and apolipoproteins A-I, A-II, C-I and C-III.

Based on this work, Dayhoff and her coworkers developed a set of substitution matrices called the PAM (Percent Accepted Mutation), MDM (Mutation Data Matrix), or Dayhoff Matrix.

They are derived from global alignments of closely related protein sequences.

The identification number included with the matrix (ex. PAM40, PAM100) refers to the evolutionary distance; greater numbers correspond to greater distances.

Matrices using greater evolutionary distances are extrapolated from those used for lesser ones.

To produce a Dayhoff matrix, pairs of aligned amino acids in verified alignments are used to build a count matrix, which is then used to estimate at mutation matrix at 1 PAM (considered an evolutionary unit).

From this mutation matrix, a Dayhoff scoring matrix may be constructed.

Along with a model of indel events, alignments generated by these methods can be used in an iterative process to construct new count matrices until convergence.

Dayhoff also taught physiology and biophysics at Georgetown University Medical Center for 13 years, served as a Fellow of the American Association for the Advancement of Science and was elected councillor of the International Society for the Study of the Origins of Life in 1980 after 8 years of membership.

Dayhoff also served on the editorial boards of three journals: DNA, Journal of Molecular Evolution and Computers in Biology and Medicine.