Margaret Oakley Dayhoff

Margaret Belle (Oakley) Dayhoff (March 11, 1925 – February 5, 1983) was an
Margaret Oakley Dayhoff
American physical chemist and a pioneer in the field of bioinformatics.[1]
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.
Born Margaret Belle
Her PhD degree was from Columbia University in the department of chemistry,
Oakley
where she devised computational methods to calculate molecular resonance
March 11, 1925
energies of several organic compounds. She did postdoctoral studies at the
Philadelphia,
Rockefeller Institute (now Rockefeller University) and the University of Pennsylvania
Maryland, and joined the newly established National Biomedical Research
Died February 5, 1983
Foundation in 1959. She was the first woman to hold office in the Biophysical
(aged 57)
Society and the first person to serve as both secretary and eventually
Silver Spring,
president.[2]
Maryland
Known for Substitution
Early life matrices
Dayhoff was born an only child in Philadelphia, but moved to New York City one-letter code
when she was ten.[3] Her academic promise was evident from the outset – she Scientific career
was valedictorian (class of 1942) at Bayside High School, Bayside, New York,
Fields Bioinformatics
and from there received a scholarship to Washington Square College of New
Institutions Columbia University
York University, graduating magna cum laude in mathematics in 1945 and
getting elected to Phi Beta Kappa.[4][5] Doctoral Duncan A.
advisor MacInnes

Research
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.[6][7] Washington
Square Park, near
After completing her PhD, Dayhoff studied electrochemistry under Duncan A. MacInnes at the where Dayhoff's
Rockefeller Institute from 1948 to 1951. In 1952, she moved to Maryland with her family and undergraduate
later received research fellowships from the University of Maryland (1957–1959), working on a work was
model of chemical bonding with Ellis Lippincott. At Maryland, she gained her first exposure to a conducted
new high-speed computer, the IBM model 7094. After this ended, she joined the National
Biomedical Research Foundation in 1960 as associate director (a position she held for 21
years).[5] 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."[8] 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. They actually began this work in 1958, but were not able to start
programming until late 1960.[8]

In the early 1960s, Dayhoff also collaborated with Ellis Lippincott and Carl
Sagan to develop thermodynamic models of cosmo-chemical systems, including An example of a pre-computer
prebiological planetary atmospheres. She developed a computer program that punch card system
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).[2] Comparison of Atmosphere
Compositions – Venus, Mars, Earth
Dayhoff also taught physiology and biophysics at Georgetown University (past and present)
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.[2]

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
An example of a computer
sarcoma viruses; antithrombin-III, alpha-antitrypsin, and ovalbumin; epidermal
generated phylogeny for MAPK
growth factor and the light chain of coagulation factor X; and apolipoproteins A-
I, A-II, C-I and C-III.[2]

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.[9] 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.[10]

One of Dayhoff's most important contributions to bioinformatics was her Atlas of Protein Sequence and Structure, a
book reporting all known protein sequences (totaling 65) that she published in 1965.[11] This book published a
degenerate encoding of amino acids. It was subsequently republished in several editions. This led to the Protein
Information Resource database of protein sequences, the first online database system that could be accessed by
telephone line and available for interrogation by remote computers.[12] The book has since been cited nearly 4,500
times.[2] It and the parallel effort by Walter Goad which led to the GenBank database of nucleic acid sequences are the
twin origins of the modern databases of molecular sequences. The Atlas was organized by gene families, and she is
regarded as a pioneer in their recognition. Frederick Sanger's determination of the first complete amino acid sequence
of a protein (insulin) in 1955, led a number of researchers to sequence various proteins from different species. In the
early 1960s, a theory was developed that small differences between homologous protein sequences (sequences with a
high likelihood of common ancestry) could indicate the process and rate of evolutionary change on the molecular level.
The notion that such molecular analysis could help scientists decode evolutionary patterns in organisms was formalized
in the published papers of Emile Zuckerkandl and Linus Pauling in 1962 and 1965.

Table of Dayhoff's encoding of amino acids

1-letter
Amino acids 3-letter code Property Dayhoff
code

Sulfur
Cysteine C Cys a
polymerization
Gly, Ser, Thr, Ala,
Glycine, Serine, Threonine, Alanine, Proline G, S, T, A, P Small b
Pro

Aspartic acid, Glutamic acid, Asparagine,

D, E, N, Q Asp, Glu, Asn, Gln Acid and amide c
Glutamine

Arginine, Histidine, Lysine R, H, K Arg, His, Lys Basic d

Leucine, Valine, Methionine, Isoleucine L, V, M, I Leu, Val, Met, Ile Hydrophobic e

Tyrosine, Phenylalanine, Tryptophan Y, F, W Tyr, Phe, Trp Aromatic f

David Lipman, director of the National Center for Biotechnology Information, has called Dayhoff the "mother and
father of bioinformatics".[13]

Marriage and family

Dayhoff's husband was Edward S. Dayhoff, an experimental physicist who worked with magnetic resonance and with
lasers.[14] They had two daughters who are also academics, Ruth and Judith.[15]

Judith Dayhoff has a Mathematical Biophysics PhD from University of Pennsylvania and is the author of Neural
network architectures: An introduction and coauthor of Neural Networks and Pattern Recognition.[15][16][17][18]

Ruth Dayhoff graduated summa cum laude in Mathematics from the University of Maryland and focused on Medical
Informatics while doing her MD at Georgetown University School of Medicine.[14] During medical school, she co-
authored a paper and a chapter in The Atlas of Protein Sequence and Structure with her mother, describing a new way to
measure how closely proteins are related.[14] Her husband Vincent Brannigan is Professor Emeritus of Law and
Technology at the University of Maryland School of Engineering. Ruth was a founding Fellow of the American College
of Medical Informatics. She pioneered the integration of Medical Imaging and invented the Vista Imaging System. She
was chosen for the National Library of Medicine's project on the 200 women Physicians who "changed the face of
medicine."[14] She serves as director of Digital Imaging in Medicine for the United States Department of Veteran's
Affairs.[5]

Later life
Dayhoff's Atlas became a template for many indispensable tools in large portions of DNA or protein-related biomedical
research. In spite of this significant contribution, Dayhoff was marginalized by the community of sequencers. The
contract to manage GenBank (a technology directly related to her research), awarded in the early 1980s by the NIH,
went to Walter Goad at the Los Alamos National Laboratory. The reason for this attitude was unknown, with theories
ranging from sexism to a clash of values with the experimental science community.[19] Despite the success of Dayhoff's
Atlas, experimental scientists and researchers considered their sequence information very valuable and were often
reluctant to submit it to such a publicly available database.[20]

During the last few years of her life, she focused on obtaining stable, adequate, long-term funding to support the
maintenance and further development of her Protein Information Resource. She envisioned an online system of
computer programs and databases, accessible by scientists all over the world, for identifying protein from sequence or
amino acid composition data, for making predictions based on sequences, and for browsing the known information.
Less than a week before she died, she submitted a proposal to the Division of Research Resources at NIH for a Protein
Identification Resource. After her death, her colleagues worked to make her vision a reality, and the protein database
was fully operational by the middle of 1984.[2]

Dayhoff died of a heart attack at the age of 57 on February 5, 1983.[3] A fund was
established after her death in 1984 to endow the Margaret O. Dayhoff Award, one of
the top national honors in biophysics. The award is presented to a woman who "holds
very high promise or has achieved prominence while developing the early stages of a
career in biophysical research within the purview and interest of the Biophysical
Society."[21] It is presented at the annual meeting of the Biophysical Society and
Logo of the Biophysical
includes an honorarium of $2,000. Society

She was survived by her husband, Edward S. Dayhoff of Silver Spring; two daughters,
Ruth E. Dayhoff Brannigan of College Park, and Judith E. Dayhoff of Silver Spring, and her father, Kenneth W. Oakley
of Silver Spring.[5]

Her seminal contributions as the mother of the science of bioinformatics, now routinely used as part of the process for
naming bacteria, were acknowledged with a bacterium being named after her in 2020, Enemella dayhoffiae.[22]

References
1. Hunt, Lois T. (1983). "Margaret O. Dayhoff 1925–1983". DNA and Cell Biology. 2 (2): 97–98.
doi:10.1089/dna.1983.2.97 (https://doi.org/10.1089%2Fdna.1983.2.97). ISSN 0198-0238 (https://www.wo
rldcat.org/issn/0198-0238). PMID 6347589 (https://pubmed.ncbi.nlm.nih.gov/6347589).
2. "Margaret Oakley Dayhoff 1925–1983". Bulletin of Mathematical Biology. 46 (4): 467–472. July 1, 1984.
doi:10.1007/BF02459497 (https://doi.org/10.1007%2FBF02459497). ISSN 0092-8240 (https://www.world
cat.org/issn/0092-8240). S2CID 189887501 (https://api.semanticscholar.org/CorpusID:189887501).
3. Windsor, Laura Lynn (January 1, 2002). Women in Medicine: An Encyclopedia (https://books.google.co
m/books?id=QtZtkf35CF0C&q=margaret+oakley+dayhoff+husband&pg=PA57). ABC-CLIO. ISBN 978-1-
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4. "American National Biography Online" (http://www.anb.org/articles/13/13-02174.html). www.anb.org.
Archived (https://web.archive.org/web/20200424081735/http://www.anb.org/articles/13/13-02174.html)
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5. "Biomedical Researcher Margaret Dayhoff Dies" (https://www.washingtonpost.com/archive/local/1983/02/
08/biomedical-researcher-margaret-dayhoff-dies/bc471417-bd61-46ac-8564-cc8dcfd05858/). The
Washington Post. February 8, 1983. ISSN 0190-8286 (https://www.worldcat.org/issn/0190-8286).
Archived (https://archive.today/20210328093945/https://www.washingtonpost.com/archive/local/1983/02/
08/biomedical-researcher-margaret-dayhoff-dies/bc471417-bd61-46ac-8564-cc8dcfd05858/) from the
original on March 28, 2021. Retrieved October 20, 2016.
6. November, Joseph A. (May 22, 2012). Biomedical Computing: Digitizing Life in the United States (https://
books.google.com/books?id=L5CmhBjwMakC&q=Watson+Computing+Laboratory+Fellowship+dayhoff&
pg=PT354). JHU Press. ISBN 978-1-4214-0665-7.
7. Krawitz, Eleanor (1949). "The Watson Scientific Laboratory" (http://www.columbia.edu/cu/computinghisto
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053146/http://www.columbia.edu/cu/computinghistory/krawitz/index.html) from the original on May 23,
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8. "Margaret Dayhoff, a founder of the field of bioinformatics | The OpenHelix Blog" (https://web.archive.org/
web/20190330155958/http://blog.openhelix.eu/?p=1078). blog.openhelix.eu. Archived from the original (h
ttp://blog.openhelix.eu/?p=1078) on March 30, 2019. Retrieved October 20, 2016.
 9. "Substitution Matrices" (http://arep.med.harvard.edu/seqanal/submatrix.html). arep.med.harvard.edu.
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html) from the original on January 30, 1998. Retrieved October 22, 2016.
10. "How to Compute Mutation and Dayhoff Matrices" (http://www.biorecipes.com/Dayhoff/code.html).
www.biorecipes.com. Archived (https://web.archive.org/web/20051127180456/http://www.biorecipes.com/
Dayhoff/code.html) from the original on November 27, 2005. Retrieved October 22, 2016.
11. "MARGARET OAKLEY DAYHOFF, 57; EXPERT ON PROTEIN STRUCTURES" (https://www.nytimes.co
m/1983/02/09/obituaries/margaret-oakley-dayhoff-57-expert-on-protein-structures.html). The New York
Times. February 9, 1983. ISSN 0362-4331 (https://www.worldcat.org/issn/0362-4331). Archived (https://w
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12. "Oakley Margaret Dayhoff | Biographical summary" (http://www.whatisbiotechnology.org/people/Dayhoff).
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13. Moody, Glyn (2004). Digital Code of Life: How Bioinformatics is Revolutionizing Science, Medicine, and
Business (https://archive.org/details/digitalcodeoflif0000mood). John Wiley & Sons. ISBN 978-0-471-
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ne/physicians/biography_76.html). www.nlm.nih.gov. Archived (https://web.archive.org/web/2016051312
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15. Levy, Rachel (March 7, 2013). "Margaret & Ruth Dayhoff" (https://ggstem.wordpress.com/2013/03/07/ma
rgaret-ruth-dayhoff/). Grandma Got STEM. Archived (https://web.archive.org/web/20161019095818/http
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16. Judith Dayhoff (https://mathgenealogy.org/id.php?id=15212) at the Mathematics Genealogy Project
17. Dayhoff, Judith E. (1990). Neural network architectures : an introduction (https://archive.org/details/neural
networkarc00dayh). New York, N.Y.: Van Nostrand Reinhold. ISBN 978-0442207441.
18. Dayhoff, Judith (1998). Omidvar, Omid (ed.). Neural networks and pattern recognition. San Diego, Calif.:
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19. Strasser, Bruno J. (December 24, 2009). "Collecting, Comparing, and Computing Sequences: The
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ISBN 978-0470016176.
21. Society, Biophysical. "Society Awards" (http://www.biophysics.org/AwardsFunding/SocietyAwards/tabid/4
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22. Bernard, Kathryn A.; Burdz, Tamara; Pacheco, Ana Luisa; Wiebe, Deborah; Patel, Nisha B.; Lawson,
Paul A.; Domingo, Marc-Christian; Longtin, Jean; Bernier, Anne-MarieYR 2020 (2020). "Enemella gen.
nov., Enemella evansiae sp. nov., Enemella dayhoffiae sp. nov. and Parenemella sanctibonifatiensis gen.
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External links
Picture of Margaret Oakley Dayhoff, c. 1980. (https://www.nlm.nih.gov/changingthefaceofmedicine/galler
y/photo_76_7.html) Owned by her daughter Ruth E. Dayhoff, M.D. Made available by the National
 Library of Medicine.
Profile and photographs of Margaret O. Dayhoff in Grandma got STEM project. (http://ggstem.wordpress.
com/2013/03/07/margaret-ruth-dayhoff/) Information submitted to the project by Margaret Dayhoff's son-
in-law Vincent, husband of Ruth E. Dayhoff. Also contains biographical information about descendants.
Baby Joseph and Vrundha M. Nair .2012 Woman Innovator in Bioinformatics: Dr. Margaret Oakley
Dayhoff. Adv Bio Tech:12 (01) 32–34

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