{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:19Z","timestamp":1792790359122,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Genomics","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Simons Foundation","award":["718235"],"award-info":[{"award-number":["718235"]}],"id":[{"id":"https:\/\/ror.org\/01cmst727","id-type":"ROR","asserted-by":"crossref"}]},{"award":["HQ Special Ops"],"award-info":[{"award-number":["HQ Special Ops"]}],"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Allergy and Infectious Diseases","award":["5R01AI165755"],"award-info":[{"award-number":["5R01AI165755"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"European Molecular Biology Organization","award":["EMBO ALTF 1103-2019"],"award-info":[{"award-number":["EMBO ALTF 1103-2019"]}],"id":[{"id":"https:\/\/ror.org\/04wfr2810","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Amino acid composition within a proteome is conventionally viewed as a property of individual protein function. However, specific nutrient scarcity has been shown to reshape which amino acids are encoded in the genome of microbes. Mosquitoes have fed on blood for 200 million years, relying on blood amino acids for reproduction. We wondered whether this ancient dependency has left an imprint on the mosquito proteome. Here we show a proteome-wide shift to lower isoleucine usage in blood-feeding mosquitoes, mirroring the known isoleucine deficiency of adult human hemoglobin. In comparing amino acid composition across the proteomes of blood-feeding and non-blood-feeding mosquitoes, we found that blood feeders show systematically lower isoleucine usage and that highly expressed gut enzymes that digest the blood meal are nearly isoleucine free. Analysis of 707 vertebrate genomes reveals that isoleucine deficiency in major hemoglobin subunits is shared among mammals. Specifically, all non-Malagasy primates, including humans, lack isoleucine in their adult hemoglobin subunits while retaining it in fetal and embryonic subunits. We find that two other major blood proteins, serum albumin and immunoglobulin G, also have reduced isoleucine levels (\u223c1.4%) compared to the human proteome-wide average of 4.38%. Finally, we reasoned that this widespread isoleucine restriction could serve to defend adult red blood cells against isoleucine-dependent blood parasites that feed on them. We tested this hypothesis with the malaria parasite\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  , which is known to arrest growth in adult red blood cells when extracellular isoleucine is withdrawn. We found that neonatal red blood cells purified from umbilical cord blood, which contain isoleucine-rich fetal hemoglobin, permit growth without extracellular isoleucine. This work demonstrates that nutritional scarcity is reflected in the genomes of animals, and that amino acid depletion of host protein sequences may serve a protective function against blood parasites.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.753855","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:50:19Z","timestamp":1790279419000},"source":"Crossref","is-referenced-by-count":0,"title":["Isoleucine absence from adult human hemoglobin is mirrored in mosquito proteomes and limits malaria parasite growth"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2903-5082","authenticated-orcid":false,"given":"Leah","family":"Houri-Zeevi","sequence":"first","affiliation":[{"name":"Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY 10065 USA"},{"name":"Howard Hughes Medical Institute, New York, NY 10065 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5476-3271","authenticated-orcid":false,"given":"Martin","family":"Kampmann","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8534-5515","authenticated-orcid":false,"given":"Manoj T.","family":"Duraisingh","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6060-8099","authenticated-orcid":false,"given":"Leslie B.","family":"Vosshall","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY 10065 USA"},{"name":"Howard Hughes Medical Institute, New York, NY 10065 USA"},{"name":"Kavli Neural Systems Institute, The Rockefeller University, New York, NY 10065 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092817253312000_2026.09.23.753855v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/341245a0"},{"key":"2026092817253312000_2026.09.23.753855v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz9642"},{"key":"2026092817253312000_2026.09.23.753855v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41764-y"},{"key":"2026092817253312000_2026.09.23.753855v1.4","doi-asserted-by":"publisher","DOI":"10.1079\/9780851993744.0020"},{"key":"2026092817253312000_2026.09.23.753855v1.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.en.37.010192.002025"},{"key":"2026092817253312000_2026.09.23.753855v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1910(90)90118-Y"},{"key":"2026092817253312000_2026.09.23.753855v1.7","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/0006-3002(57)90261-5","article-title":"Observations on the amino acid composition of human hemoglobins","volume":"24","year":"1957","journal-title":"Biochimica et Biophysica Acta"},{"key":"2026092817253312000_2026.09.23.753855v1.8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13071-021-04594-9","article-title":"Whole blood and blood components from vertebrates differentially affect egg formation in three species of anautogenous mosquitoes","volume":"14","year":"2021","journal-title":"Parasites Vectors"},{"key":"2026092817253312000_2026.09.23.753855v1.9","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0300-9629(77)90342-5","article-title":"The role of isoleucine in differential egg production by the mosquito Aedes aegypti Linnaeus (Diptera: Culicidae) following feeding on human or guinea pig blood","volume":"57","year":"1977","journal-title":"Comparative Biochemistry and Physiology Part A: Physiology"},{"key":"2026092817253312000_2026.09.23.753855v1.10","doi-asserted-by":"crossref","unstructured":"Houri-Zeevi, L. , et al. 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