Multiple mutations of SARS-CoV-2 Omicron BA.2 variant orchestrate its virological characteristics
Authors: Kimura Izumi , Yamasoba Daichi , Nasser Hesham , Ito Hayato , Zahradnik Jiri , Wu Jiaqi , Fujita Shigeru , Uriu Keiya , Sasaki Jiei , Tamura Tomokazu , Suzuki Rigel , Deguchi Sayaka , Plianchaisuk Arnon , Yoshimatsu Kumiko , Kazuma Yasuhiro , Mitoma Shuya , Schreiber Gideon , Asakura Hiroyuki , Nagashima Mami , Sadamasu Kenji , Yoshimura Kazuhisa , Takaori-Kondo Akifumi ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Shirakawa Kotaro , Takayama Kazuo , Irie Takashi , Hashiguchi Takao , Nakagawa So , Fukuhara Takasuke , Saito Akatsuki , Ikeda Terumasa , Sato Kei , Misawa Naoko , Kosugi Yusuke , Pan Lin , Suganami Mai , Chiba Mika , Yoshimura Ryo , Yasuda Kyoko , Iida Keiko , Ohsumi Naomi , Strange Adam P. , Kaku Yu , Plianchaisuk Arnon , Guo Ziyi , Hinay Alfredo Jr. Amolong , Mendoza Tolentino Jarel Elgin , Chen Luo , Shimizu Ryo , Monira Begum M. S. T. , Takahashi Otowa , Ichihara Kimiko , Jonathan Michael , Mugita Yuka , Suzuki Saori , Suzuki Tateki , Kimura Kanako , Nakajima Yukari , Yajima Hisano , Hashimoto Rina , Watanabe Yukio , Sakamoto Ayaka , Yasuhara Naoko , Nagata Kayoko , Nomura Ryosuke , Horisawa Yoshihito , Tashiro Yusuke , Kawai Yugo , Shibatani Yuki , Nishiuchi Tomoko , Yoshida Isao , Kawabata Ryoko , Matsuno Keita , Nao Naganori , Sawa Hirofumi , Tanaka Shinya , Tsuda Masumi , Wang Lei , Oda Yoshikata , Ferdous Zannatul , Shishido Kenji , Motozono Chihiro , Toyoda Mako , Ueno Takamasa , Tabata Kaori 
Published: October 2023

ABSTRACT

Previous studies on the Omicron BA.2 variant suggested that the virological characteristics of BA.2 are determined by the mutations in at least two different regions of the viral genome: in the BA.2
spike
gene (enhancing viral fusogenicity and intrinsic pathogenicity) and the non-
spike
region of the BA.2 genome (leading to intrinsic pathogenicity attenuation). However, the mutations modulating the BA.2 virological properties remain elusive. In this study, we demonstrated that the L371F substitution in the BA.2 spike protein confers greater fusogenicity and intrinsic pathogenicity. Furthermore, we revealed that multiple mutations downstream of the
spike
gene in the BA.2 genome are responsible for attenuating intrinsic viral pathogenicity and replication capacity. As mutations in the SARS-CoV-2 variant spike proteins could modulate certain virological properties, such as immune evasion and infectivity, most studies have previously focused on spike protein mutations. Our results underpin the importance of non-spike protein-related mutations in SARS-CoV-2 variants.

Importance

Most studies investigating the characteristics of emerging SARS-CoV-2 variants have been focusing on mutations in the spike proteins that affect viral infectivity, fusogenicity, and pathogenicity. However, few studies have addressed how naturally occurring mutations in the non-
spike
regions of the SARS-CoV-2 genome impact virological properties. In this study, we proved that multiple SARS-CoV-2 Omicron BA.2 mutations, one in the spike protein and another downstream of the
spike
gene, orchestrally characterize this variant, shedding light on the importance of Omicron BA.2 mutations out of the spike protein.